The Food and Drug Administration has approved the combination of nivolumab (Opdivo), ipilimumab (Yervoy), and two cycles of platinum-doublet chemotherapy as frontline treatment for patients with metastatic or recurrent non–small cell lung cancer (NSCLC) who have no EGFR or ALK genomic tumor aberrations.

The FDA collaborated with the Australian Therapeutic Goods Administration, Health Canada, and Singapore’s Health Sciences Authority on the review that led to this approval, as part of Project Orbis. The FDA approved the application 2 months ahead of schedule.

The combination chemotherapy was investigated in the CHECKMATE-9LA trial (NCT03215706), which enrolled patients with metastatic or recurrent NSCLC.

Patients were randomized to receive nivolumab plus ipilimumab and two cycles of platinum-doublet chemotherapy (n = 361) or platinum-doublet chemotherapy for four cycles (n = 358).

There was a significant overall survival benefit in the nivolumab-ipilimumab arm, compared with the chemotherapy-only arm. The median overall survival was 14.1 months and 10.7 months, respectively (hazard ratio, 0.69; P = .0006).

The median progression-free survival was 6.8 months in the nivolumab-ipilimumab arm and 5 months in the chemotherapy-only arm (HR, 0.70; P = .0001). The overall response rate was 38% and 25%, respectively (P = .0003).

The most common adverse events in the nivolumab-ipilimumab arm, which occurred in at least 20% of patients, were fatigue, musculoskeletal pain, nausea, diarrhea, rash, decreased appetite, constipation, and pruritus.

Serious adverse events occurred in 57% of patients in the nivolumab-ipilimumab arm. Fatal adverse events occurred in seven patients (2%) in that arm. Fatal events were hepatic toxicity, acute renal failure, sepsis, pneumonitis, diarrhea with hypokalemia, and massive hemoptysis in the setting of thrombocytopenia.

For more details, see the full prescribing information for nivolumab or ipilimumab. Nivolumab and ipilimumab are both products of Bristol-Myers Squibb.

The Food and Drug Administration has approved the combination of nivolumab (Opdivo), ipilimumab (Yervoy), and two cycles of platinum-doublet chemotherapy as frontline treatment for patients with metastatic or recurrent non–small cell lung cancer (NSCLC) who have no EGFR or ALK genomic tumor aberrations.

The FDA collaborated with the Australian Therapeutic Goods Administration, Health Canada, and Singapore’s Health Sciences Authority on the review that led to this approval, as part of Project Orbis. The FDA approved the application 2 months ahead of schedule.

The combination chemotherapy was investigated in the CHECKMATE-9LA trial (NCT03215706), which enrolled patients with metastatic or recurrent NSCLC.

Patients were randomized to receive nivolumab plus ipilimumab and two cycles of platinum-doublet chemotherapy (n = 361) or platinum-doublet chemotherapy for four cycles (n = 358).

There was a significant overall survival benefit in the nivolumab-ipilimumab arm, compared with the chemotherapy-only arm. The median overall survival was 14.1 months and 10.7 months, respectively (hazard ratio, 0.69; P = .0006).

The median progression-free survival was 6.8 months in the nivolumab-ipilimumab arm and 5 months in the chemotherapy-only arm (HR, 0.70; P = .0001). The overall response rate was 38% and 25%, respectively (P = .0003).

The most common adverse events in the nivolumab-ipilimumab arm, which occurred in at least 20% of patients, were fatigue, musculoskeletal pain, nausea, diarrhea, rash, decreased appetite, constipation, and pruritus.

Serious adverse events occurred in 57% of patients in the nivolumab-ipilimumab arm. Fatal adverse events occurred in seven patients (2%) in that arm. Fatal events were hepatic toxicity, acute renal failure, sepsis, pneumonitis, diarrhea with hypokalemia, and massive hemoptysis in the setting of thrombocytopenia.

For more details, see the full prescribing information for nivolumab or ipilimumab. Nivolumab and ipilimumab are both products of Bristol-Myers Squibb.

The Food and Drug Administration has approved the combination of nivolumab (Opdivo), ipilimumab (Yervoy), and two cycles of platinum-doublet chemotherapy as frontline treatment for patients with metastatic or recurrent non–small cell lung cancer (NSCLC) who have no EGFR or ALK genomic tumor aberrations.

The FDA collaborated with the Australian Therapeutic Goods Administration, Health Canada, and Singapore’s Health Sciences Authority on the review that led to this approval, as part of Project Orbis. The FDA approved the application 2 months ahead of schedule.

The combination chemotherapy was investigated in the CHECKMATE-9LA trial (NCT03215706), which enrolled patients with metastatic or recurrent NSCLC.

Patients were randomized to receive nivolumab plus ipilimumab and two cycles of platinum-doublet chemotherapy (n = 361) or platinum-doublet chemotherapy for four cycles (n = 358).

There was a significant overall survival benefit in the nivolumab-ipilimumab arm, compared with the chemotherapy-only arm. The median overall survival was 14.1 months and 10.7 months, respectively (hazard ratio, 0.69; P = .0006).

The median progression-free survival was 6.8 months in the nivolumab-ipilimumab arm and 5 months in the chemotherapy-only arm (HR, 0.70; P = .0001). The overall response rate was 38% and 25%, respectively (P = .0003).

The most common adverse events in the nivolumab-ipilimumab arm, which occurred in at least 20% of patients, were fatigue, musculoskeletal pain, nausea, diarrhea, rash, decreased appetite, constipation, and pruritus.

Serious adverse events occurred in 57% of patients in the nivolumab-ipilimumab arm. Fatal adverse events occurred in seven patients (2%) in that arm. Fatal events were hepatic toxicity, acute renal failure, sepsis, pneumonitis, diarrhea with hypokalemia, and massive hemoptysis in the setting of thrombocytopenia.

For more details, see the full prescribing information for nivolumab or ipilimumab. Nivolumab and ipilimumab are both products of Bristol-Myers Squibb.

Roughly 16%-22% of patients with hypertension appeared to have primary aldosteronism as the likely major cause of their elevated blood pressure, in an analysis of about 1,000 Americans, which is a much higher prevalence than previously appreciated and a finding that could potentially reorient both screening for aldosteronism and management for this subset of patients.

“Our findings show a high prevalence of unrecognized yet biochemically overt primary aldosteronism [PA] using current confirmatory diagnostic thresholds. They highlight the inadequacy of the current diagnostic approach that heavily relies on the ARR [aldosterone renin ratio] and, most important, show the existence of a pathologic continuum of nonsuppressible renin-independent aldosterone production that parallels the severity of hypertension,” wrote Jennifer M. Brown, MD, and coinvestigators in a report published in Annals of Internal Medicine on May 25. “These findings support the need to redefine primary aldosteronism from a rare and categorical disease to, instead, a common syndrome that manifests across a broad severity spectrum and may be a primary contributor to hypertension pathogenesis,” they wrote in the report.

The results, showing an underappreciated prevalence of both overt and subtler forms of aldosteronism that link with hypertension, won praise from several experts for the potential of these findings to boost the profile of excess aldosterone as a common and treatable cause of high blood pressure, but opinions on the role for the ARR as a screen to identify affected patients were more mixed.

“ARR is still the best screening approach we have” for identifying people who likely have PA, especially when the ratio threshold for finding patients who need further investigation is reduced from the traditional level of 30 ng/dL to 20 ng/dL, commented Michael Stowasser, MBBS, professor of medicine at the University of Queensland in Brisbane, Australia, and director of the Endocrine Hypertension Research Centre at Greenslopes and Princess Alexandra Hospitals in Brisbane. “I strongly recommend ARR testing in all newly diagnosed hypertensives.”

The study results “showed that PA is much more common than previously perceived, and suggest that perhaps PA in milder forms than we typically recognize contributes more to ‘essential’ hypertension than we previously thought,” said Anand Vaidya, MD, senior author of the report and director of the Center for Adrenal Disorders at Brigham and Women’s Hospital in Boston. The researchers found adjusted PA prevalence rates of 16% among 115 untreated patients with stage 1 hypertension (130-139/80-89 mm Hg), 22% among 203 patients with untreated stage 2 hypertension (at least 140/90 mm Hg), and 22% among 408 patients with treatment-resistant hypertension. All three prevalence rates were based on relatively conservative criteria that included all 726 patients with hypertension in the analysis (which also included 289 normotensive subjects) regardless of whether or not they also had low levels of serum renin. These PA prevalence rates were also based on a “conservative” definition of PA, a level of at least 12 mcg excreted in a 24-hour urine specimen.

When the researchers applied less stringent diagnostic criteria for PA or focused on the types of patients usually at highest risk for PA because of a suppressed renin level, the prevalence rates rose substantially and, in some subgroups, more than doubled. Of the 726 people with hypertension included in the analysis, 452 (62%) had suppressed renin (seated plasma renin activity < 1.0 mcg/L per hour or supine plasma renin activity < 0.6 mcg/L per hour). Within this subgroup of patients with suppressed renin, the adjusted prevalence of PA by the threshold of 24-hour urine aldosterone secretion of at least 12 mcg was 52% in those with treatment-resistant hypertension; among patients with stage 1 or 2 hypertension the adjusted prevalence rates were just slightly above the rates in the entire study group. But among patients with suppressed renin who were judged to have PA by a more liberal definition of at least 10 mcg in a 24-hour urine sample, the adjusted prevalence rates were 27% among untreated stage 1 hypertensives, 40% among untreated stage 2 patients, and 58% among treatment-resistant patients, the report showed.
 

A role for subtler forms of aldosteronism

Defining PA as at least 12 mcg secreted in a 24-hour urine collection “is relatively arbitrary, and our findings show that it bisects a continuous distribution. How we should redefine PA is also arbitrary, but step one is to recognize that many people have milder forms of PA” that could have an important effect on blood pressure, Dr. Vaidya said in an interview.

“This is the very first study to show that aldosterone may be contributing to the hypertensive process even though it is not severe enough to be diagnosed as PA according to current criteria,” said Robert M. Carey, MD, a cardiovascular endocrinologist and professor of medicine at the University of Virginia in Charlottesville and a coauthor on the new report. “More patients than we have ever known have an aldosterone component to their hypertension,” Dr. Carey said in an interview.

The new report on the prevalence of unrecognized PA in hypertensive patients “is a game changer,” wrote John W. Funder, MD, professor of medicine at Monash University in Clayton, Australia, in an editorial published along with the new report. In the editorial, he synthesized the new findings with results from prior reports to estimate that excess aldosteronism could play a clinically meaningful role in close to half of patients with hypertension, although Dr. Stowasser called this an “overestimate.” The new results also showed that “the single spot measurement of plasma aldosterone concentration, which clinicians have used for decades to screen for primary aldosteronism, is not merely useless but actually misleading. The authors cautioned readers about the uncertain representativeness of the study population to the U.S. population, but I believe that the findings are generalizable to the United States and elsewhere,” Dr. Funder wrote. “The central problem is that plasma aldosterone concentration is a very poor index of total daily aldosterone secretion. A single morning spot measurement of plasma aldosterone cannot take into account ultradian variation in aldosterone secretion.”
 

The importance of finding excess aldosterone

Identifying patients with hypertension and PA, as well as hypertensives with excess aldosterone production that may not meet the traditional definition of PA, is especially important because they are excellent candidates for two forms of targeted and very effective treatments that have a reliable and substantial impact on lowering blood pressure in these patients. One treatment is unilateral adrenal gland removal in patients who produce excess aldosterone because of benign adenomas in one adrenal gland, which accounts for “approximately 30%” of patients with PA. “Patients with suspected PA should have an opportunity to find out whether they have a unilateral variety and chance for surgical cure,” said Dr. Stowasser in an interview. “Patients with PA do far better in terms of blood pressure control, prevention of cardiovascular complications, and quality of life if they are treated specifically, either medically or particularly by surgery.”

The specific medical treatment he cited refers to one of the mineralocorticoid receptor antagonist (MRA) drugs, spironolactone and eplerenone (Inspra), because mineralocorticoid receptor blockade directly short-circuits the path by which aldosterone increases blood pressure. “We’re advocating earlier use of MRAs” for hypertensive patients identified with excess aldosterone production, said Dr. Carey. He noted that alternative, nonsteroidal MRAs, such as finerenone, have shown promise for efficacy levels similar to what spironolactone provides but without as many adverse effects because of greater receptor specificity. Finerenone and other nonsteroidal MRAs are all currently investigational. Spironolactone and eplerenone both cause hyperkalemia, although treatment with potassium binding agents can blunt the risk this poses. Spironolactone also causes bothersome adverse effects in men, including impotence and gynecomastia because of its action on androgen receptors, effects that diminished with eplerenone, but eplerenone is not as effective as spironolactone, Dr. Carey said.
 

Study details

The new study ran a post hoc analysis on data collected in five independent studies run at centers in four U.S. locations: Birmingham, Ala.; Boston; Charlottesville, Va.; and Salt Lake City. The studies included a total of 1,846 adults, mostly patients with hypertension of varying severity but also several hundred normotensive people. Data on 24-hour sodium excretion during an oral sodium suppression test were available for all participants, and the researchers excluded 831 people with an “inadequate” sodium balance of less than 190 mmol based on this metric, leaving a study population of 1,015. The researchers acknowledged the limitation that the study participants were not representative of the U.S. population.

The analysis included 289 normotensive people not on any blood pressure–lowering medications, and 239 fit the definition of having suppressed renin. The adjusted prevalence of aldosteronism at the level of at least 12 mcg excreted in a 24-hour urine specimen was 11% among all 289 normotensive subjects and 12% among the 239 with suppressed renin. When the definition of aldosteronism loosened to at least 10 mcg excreted during 24 hours the adjusted prevalence of excess aldosterone among normotensives increased to 19% among the entire group and 20% among those with suppressed renin. This finding may have identified a primordial phase of nascent hypertension that needs further study but may eventually provide a new scenario for intervention. “If a normotensive person has compliant arteries and healthy kidneys they can handle the excess salt and volume load of PA,” but when compensatory mechanisms start falling short through aging or other deteriorations, then blood pressure starts to rise, suggested Dr. Vaidya.
 

Whom to screen for aldosteronism and how

While several experts agreed these findings added to an existing and growing literature showing that PA is common and needs greater diagnostic attention, they differed on what this may mean for the specifics of screening and diagnosis, especially at the primary care level.

“Our results showed more explicitly that excess aldosterone exists on a broad severity spectrum and can’t be regarded as a categorical diagnosis that a patient either has or does not have. The hard part is figuring out where we should begin interventions,” said Dr. Vaidya.

In his editorial, Dr. Funder wrote that “much of the present guideline needs to be jettisoned, and radically reconstructed recommendations should be developed.”

One answer may be to apply a less stringent ARR threshold for further work-up. Dr. Stowasser’s program in Brisbane, as well as some other groups worldwide, use an ARR of at least 20 ng/dL as an indication of possible PA. “If you lower the cutoff to 20 [ng/dL], and ignore the plasma aldosterone level, then the ARR should pick up the great majority of patients with PA,” he said.

Another controversial aspect is whether aldosterone detection should be screened by 24-hour urine collection or by spot testing. In his editorial, Dr. Funder called spot testing “useless” and “misleading,” but Dr. Vaidya acknowledged that the 24-hour collection used in his current study is “not practical” for widespread use. Despite that, the Mayo Clinic in Rochester has focused on 24-hour urine collected “for more than 4 decades,” said Dr. Young, even though “a morning blood sample remains a simple screening test” that will catch “more than 95% of patients with PA” when combined with a plasma aldosterone threshold of 10 ng/dL. Dr. Stowasser noted that “patients don’t like” 24-hour collection, and not infrequently muck up collection” by forgetting to collect their entire 1-day output. Regardless of its shortcomings, 24-hour urine has the advantage of greater precision and accuracy than spot measurement, and using it on newly diagnosed hypertensive patients who also show renin suppression may be a viable approach, Dr. Carey suggested.

Regardless of exactly how guidelines for assessing aldosterone in hypertensive patients change, prospects seem ripe for some sort of revision and for greater participation and buy-in by primary care physicians than in the past. Dr. Carey, who also served as vice-chair of the American College of Cardiology and American Heart Association Task Force that wrote the most current U.S. guideline for managing hypertension, said it was too soon to revise that document, but the time had come to revise the Endocrine Society’s 2016 guideline for diagnosing and treating PA and to hash out the revision “in partnership” with one or more primary care societies. He also highlighted that publishing the current study in a high-profile primary care journal was an intentional effort to reach a large segment of the primary care community.

The new report “has the potential to change the current state of inertia” over wider PA diagnosis and targeted treatment “by being published in a widely read, major international journal,” commented Dr. Stowasser.

Dr. Vaidya has been a consultant to Catalys Pacific, Corcept Therapeutics, HRA Pharma, Orphagen, and Selenity Therapeutics. None of the other report coauthors had commercial disclosures, including Dr. Carey. Dr. Funder, Dr. Stowasser, and Dr. Young had no disclosures.

mzoler@mdedge.com

SOURCE: Brown JM et al. Ann Int Med. 2020 May 25. doi: 10.7326/M20-0065.
 

Roughly 16%-22% of patients with hypertension appeared to have primary aldosteronism as the likely major cause of their elevated blood pressure, in an analysis of about 1,000 Americans, which is a much higher prevalence than previously appreciated and a finding that could potentially reorient both screening for aldosteronism and management for this subset of patients.

“Our findings show a high prevalence of unrecognized yet biochemically overt primary aldosteronism [PA] using current confirmatory diagnostic thresholds. They highlight the inadequacy of the current diagnostic approach that heavily relies on the ARR [aldosterone renin ratio] and, most important, show the existence of a pathologic continuum of nonsuppressible renin-independent aldosterone production that parallels the severity of hypertension,” wrote Jennifer M. Brown, MD, and coinvestigators in a report published in Annals of Internal Medicine on May 25. “These findings support the need to redefine primary aldosteronism from a rare and categorical disease to, instead, a common syndrome that manifests across a broad severity spectrum and may be a primary contributor to hypertension pathogenesis,” they wrote in the report.

The results, showing an underappreciated prevalence of both overt and subtler forms of aldosteronism that link with hypertension, won praise from several experts for the potential of these findings to boost the profile of excess aldosterone as a common and treatable cause of high blood pressure, but opinions on the role for the ARR as a screen to identify affected patients were more mixed.

“ARR is still the best screening approach we have” for identifying people who likely have PA, especially when the ratio threshold for finding patients who need further investigation is reduced from the traditional level of 30 ng/dL to 20 ng/dL, commented Michael Stowasser, MBBS, professor of medicine at the University of Queensland in Brisbane, Australia, and director of the Endocrine Hypertension Research Centre at Greenslopes and Princess Alexandra Hospitals in Brisbane. “I strongly recommend ARR testing in all newly diagnosed hypertensives.”

The study results “showed that PA is much more common than previously perceived, and suggest that perhaps PA in milder forms than we typically recognize contributes more to ‘essential’ hypertension than we previously thought,” said Anand Vaidya, MD, senior author of the report and director of the Center for Adrenal Disorders at Brigham and Women’s Hospital in Boston. The researchers found adjusted PA prevalence rates of 16% among 115 untreated patients with stage 1 hypertension (130-139/80-89 mm Hg), 22% among 203 patients with untreated stage 2 hypertension (at least 140/90 mm Hg), and 22% among 408 patients with treatment-resistant hypertension. All three prevalence rates were based on relatively conservative criteria that included all 726 patients with hypertension in the analysis (which also included 289 normotensive subjects) regardless of whether or not they also had low levels of serum renin. These PA prevalence rates were also based on a “conservative” definition of PA, a level of at least 12 mcg excreted in a 24-hour urine specimen.

When the researchers applied less stringent diagnostic criteria for PA or focused on the types of patients usually at highest risk for PA because of a suppressed renin level, the prevalence rates rose substantially and, in some subgroups, more than doubled. Of the 726 people with hypertension included in the analysis, 452 (62%) had suppressed renin (seated plasma renin activity < 1.0 mcg/L per hour or supine plasma renin activity < 0.6 mcg/L per hour). Within this subgroup of patients with suppressed renin, the adjusted prevalence of PA by the threshold of 24-hour urine aldosterone secretion of at least 12 mcg was 52% in those with treatment-resistant hypertension; among patients with stage 1 or 2 hypertension the adjusted prevalence rates were just slightly above the rates in the entire study group. But among patients with suppressed renin who were judged to have PA by a more liberal definition of at least 10 mcg in a 24-hour urine sample, the adjusted prevalence rates were 27% among untreated stage 1 hypertensives, 40% among untreated stage 2 patients, and 58% among treatment-resistant patients, the report showed.
 

A role for subtler forms of aldosteronism

Defining PA as at least 12 mcg secreted in a 24-hour urine collection “is relatively arbitrary, and our findings show that it bisects a continuous distribution. How we should redefine PA is also arbitrary, but step one is to recognize that many people have milder forms of PA” that could have an important effect on blood pressure, Dr. Vaidya said in an interview.

“This is the very first study to show that aldosterone may be contributing to the hypertensive process even though it is not severe enough to be diagnosed as PA according to current criteria,” said Robert M. Carey, MD, a cardiovascular endocrinologist and professor of medicine at the University of Virginia in Charlottesville and a coauthor on the new report. “More patients than we have ever known have an aldosterone component to their hypertension,” Dr. Carey said in an interview.

The new report on the prevalence of unrecognized PA in hypertensive patients “is a game changer,” wrote John W. Funder, MD, professor of medicine at Monash University in Clayton, Australia, in an editorial published along with the new report. In the editorial, he synthesized the new findings with results from prior reports to estimate that excess aldosteronism could play a clinically meaningful role in close to half of patients with hypertension, although Dr. Stowasser called this an “overestimate.” The new results also showed that “the single spot measurement of plasma aldosterone concentration, which clinicians have used for decades to screen for primary aldosteronism, is not merely useless but actually misleading. The authors cautioned readers about the uncertain representativeness of the study population to the U.S. population, but I believe that the findings are generalizable to the United States and elsewhere,” Dr. Funder wrote. “The central problem is that plasma aldosterone concentration is a very poor index of total daily aldosterone secretion. A single morning spot measurement of plasma aldosterone cannot take into account ultradian variation in aldosterone secretion.”
 

The importance of finding excess aldosterone

Identifying patients with hypertension and PA, as well as hypertensives with excess aldosterone production that may not meet the traditional definition of PA, is especially important because they are excellent candidates for two forms of targeted and very effective treatments that have a reliable and substantial impact on lowering blood pressure in these patients. One treatment is unilateral adrenal gland removal in patients who produce excess aldosterone because of benign adenomas in one adrenal gland, which accounts for “approximately 30%” of patients with PA. “Patients with suspected PA should have an opportunity to find out whether they have a unilateral variety and chance for surgical cure,” said Dr. Stowasser in an interview. “Patients with PA do far better in terms of blood pressure control, prevention of cardiovascular complications, and quality of life if they are treated specifically, either medically or particularly by surgery.”

The specific medical treatment he cited refers to one of the mineralocorticoid receptor antagonist (MRA) drugs, spironolactone and eplerenone (Inspra), because mineralocorticoid receptor blockade directly short-circuits the path by which aldosterone increases blood pressure. “We’re advocating earlier use of MRAs” for hypertensive patients identified with excess aldosterone production, said Dr. Carey. He noted that alternative, nonsteroidal MRAs, such as finerenone, have shown promise for efficacy levels similar to what spironolactone provides but without as many adverse effects because of greater receptor specificity. Finerenone and other nonsteroidal MRAs are all currently investigational. Spironolactone and eplerenone both cause hyperkalemia, although treatment with potassium binding agents can blunt the risk this poses. Spironolactone also causes bothersome adverse effects in men, including impotence and gynecomastia because of its action on androgen receptors, effects that diminished with eplerenone, but eplerenone is not as effective as spironolactone, Dr. Carey said.
 

Study details

The new study ran a post hoc analysis on data collected in five independent studies run at centers in four U.S. locations: Birmingham, Ala.; Boston; Charlottesville, Va.; and Salt Lake City. The studies included a total of 1,846 adults, mostly patients with hypertension of varying severity but also several hundred normotensive people. Data on 24-hour sodium excretion during an oral sodium suppression test were available for all participants, and the researchers excluded 831 people with an “inadequate” sodium balance of less than 190 mmol based on this metric, leaving a study population of 1,015. The researchers acknowledged the limitation that the study participants were not representative of the U.S. population.

The analysis included 289 normotensive people not on any blood pressure–lowering medications, and 239 fit the definition of having suppressed renin. The adjusted prevalence of aldosteronism at the level of at least 12 mcg excreted in a 24-hour urine specimen was 11% among all 289 normotensive subjects and 12% among the 239 with suppressed renin. When the definition of aldosteronism loosened to at least 10 mcg excreted during 24 hours the adjusted prevalence of excess aldosterone among normotensives increased to 19% among the entire group and 20% among those with suppressed renin. This finding may have identified a primordial phase of nascent hypertension that needs further study but may eventually provide a new scenario for intervention. “If a normotensive person has compliant arteries and healthy kidneys they can handle the excess salt and volume load of PA,” but when compensatory mechanisms start falling short through aging or other deteriorations, then blood pressure starts to rise, suggested Dr. Vaidya.
 

Whom to screen for aldosteronism and how

While several experts agreed these findings added to an existing and growing literature showing that PA is common and needs greater diagnostic attention, they differed on what this may mean for the specifics of screening and diagnosis, especially at the primary care level.

“Our results showed more explicitly that excess aldosterone exists on a broad severity spectrum and can’t be regarded as a categorical diagnosis that a patient either has or does not have. The hard part is figuring out where we should begin interventions,” said Dr. Vaidya.

In his editorial, Dr. Funder wrote that “much of the present guideline needs to be jettisoned, and radically reconstructed recommendations should be developed.”

One answer may be to apply a less stringent ARR threshold for further work-up. Dr. Stowasser’s program in Brisbane, as well as some other groups worldwide, use an ARR of at least 20 ng/dL as an indication of possible PA. “If you lower the cutoff to 20 [ng/dL], and ignore the plasma aldosterone level, then the ARR should pick up the great majority of patients with PA,” he said.

Another controversial aspect is whether aldosterone detection should be screened by 24-hour urine collection or by spot testing. In his editorial, Dr. Funder called spot testing “useless” and “misleading,” but Dr. Vaidya acknowledged that the 24-hour collection used in his current study is “not practical” for widespread use. Despite that, the Mayo Clinic in Rochester has focused on 24-hour urine collected “for more than 4 decades,” said Dr. Young, even though “a morning blood sample remains a simple screening test” that will catch “more than 95% of patients with PA” when combined with a plasma aldosterone threshold of 10 ng/dL. Dr. Stowasser noted that “patients don’t like” 24-hour collection, and not infrequently muck up collection” by forgetting to collect their entire 1-day output. Regardless of its shortcomings, 24-hour urine has the advantage of greater precision and accuracy than spot measurement, and using it on newly diagnosed hypertensive patients who also show renin suppression may be a viable approach, Dr. Carey suggested.

Regardless of exactly how guidelines for assessing aldosterone in hypertensive patients change, prospects seem ripe for some sort of revision and for greater participation and buy-in by primary care physicians than in the past. Dr. Carey, who also served as vice-chair of the American College of Cardiology and American Heart Association Task Force that wrote the most current U.S. guideline for managing hypertension, said it was too soon to revise that document, but the time had come to revise the Endocrine Society’s 2016 guideline for diagnosing and treating PA and to hash out the revision “in partnership” with one or more primary care societies. He also highlighted that publishing the current study in a high-profile primary care journal was an intentional effort to reach a large segment of the primary care community.

The new report “has the potential to change the current state of inertia” over wider PA diagnosis and targeted treatment “by being published in a widely read, major international journal,” commented Dr. Stowasser.

Dr. Vaidya has been a consultant to Catalys Pacific, Corcept Therapeutics, HRA Pharma, Orphagen, and Selenity Therapeutics. None of the other report coauthors had commercial disclosures, including Dr. Carey. Dr. Funder, Dr. Stowasser, and Dr. Young had no disclosures.

mzoler@mdedge.com

SOURCE: Brown JM et al. Ann Int Med. 2020 May 25. doi: 10.7326/M20-0065.
 

Roughly 16%-22% of patients with hypertension appeared to have primary aldosteronism as the likely major cause of their elevated blood pressure, in an analysis of about 1,000 Americans, which is a much higher prevalence than previously appreciated and a finding that could potentially reorient both screening for aldosteronism and management for this subset of patients.

“Our findings show a high prevalence of unrecognized yet biochemically overt primary aldosteronism [PA] using current confirmatory diagnostic thresholds. They highlight the inadequacy of the current diagnostic approach that heavily relies on the ARR [aldosterone renin ratio] and, most important, show the existence of a pathologic continuum of nonsuppressible renin-independent aldosterone production that parallels the severity of hypertension,” wrote Jennifer M. Brown, MD, and coinvestigators in a report published in Annals of Internal Medicine on May 25. “These findings support the need to redefine primary aldosteronism from a rare and categorical disease to, instead, a common syndrome that manifests across a broad severity spectrum and may be a primary contributor to hypertension pathogenesis,” they wrote in the report.

The results, showing an underappreciated prevalence of both overt and subtler forms of aldosteronism that link with hypertension, won praise from several experts for the potential of these findings to boost the profile of excess aldosterone as a common and treatable cause of high blood pressure, but opinions on the role for the ARR as a screen to identify affected patients were more mixed.

“ARR is still the best screening approach we have” for identifying people who likely have PA, especially when the ratio threshold for finding patients who need further investigation is reduced from the traditional level of 30 ng/dL to 20 ng/dL, commented Michael Stowasser, MBBS, professor of medicine at the University of Queensland in Brisbane, Australia, and director of the Endocrine Hypertension Research Centre at Greenslopes and Princess Alexandra Hospitals in Brisbane. “I strongly recommend ARR testing in all newly diagnosed hypertensives.”

The study results “showed that PA is much more common than previously perceived, and suggest that perhaps PA in milder forms than we typically recognize contributes more to ‘essential’ hypertension than we previously thought,” said Anand Vaidya, MD, senior author of the report and director of the Center for Adrenal Disorders at Brigham and Women’s Hospital in Boston. The researchers found adjusted PA prevalence rates of 16% among 115 untreated patients with stage 1 hypertension (130-139/80-89 mm Hg), 22% among 203 patients with untreated stage 2 hypertension (at least 140/90 mm Hg), and 22% among 408 patients with treatment-resistant hypertension. All three prevalence rates were based on relatively conservative criteria that included all 726 patients with hypertension in the analysis (which also included 289 normotensive subjects) regardless of whether or not they also had low levels of serum renin. These PA prevalence rates were also based on a “conservative” definition of PA, a level of at least 12 mcg excreted in a 24-hour urine specimen.

When the researchers applied less stringent diagnostic criteria for PA or focused on the types of patients usually at highest risk for PA because of a suppressed renin level, the prevalence rates rose substantially and, in some subgroups, more than doubled. Of the 726 people with hypertension included in the analysis, 452 (62%) had suppressed renin (seated plasma renin activity < 1.0 mcg/L per hour or supine plasma renin activity < 0.6 mcg/L per hour). Within this subgroup of patients with suppressed renin, the adjusted prevalence of PA by the threshold of 24-hour urine aldosterone secretion of at least 12 mcg was 52% in those with treatment-resistant hypertension; among patients with stage 1 or 2 hypertension the adjusted prevalence rates were just slightly above the rates in the entire study group. But among patients with suppressed renin who were judged to have PA by a more liberal definition of at least 10 mcg in a 24-hour urine sample, the adjusted prevalence rates were 27% among untreated stage 1 hypertensives, 40% among untreated stage 2 patients, and 58% among treatment-resistant patients, the report showed.
 

A role for subtler forms of aldosteronism

Defining PA as at least 12 mcg secreted in a 24-hour urine collection “is relatively arbitrary, and our findings show that it bisects a continuous distribution. How we should redefine PA is also arbitrary, but step one is to recognize that many people have milder forms of PA” that could have an important effect on blood pressure, Dr. Vaidya said in an interview.

“This is the very first study to show that aldosterone may be contributing to the hypertensive process even though it is not severe enough to be diagnosed as PA according to current criteria,” said Robert M. Carey, MD, a cardiovascular endocrinologist and professor of medicine at the University of Virginia in Charlottesville and a coauthor on the new report. “More patients than we have ever known have an aldosterone component to their hypertension,” Dr. Carey said in an interview.

The new report on the prevalence of unrecognized PA in hypertensive patients “is a game changer,” wrote John W. Funder, MD, professor of medicine at Monash University in Clayton, Australia, in an editorial published along with the new report. In the editorial, he synthesized the new findings with results from prior reports to estimate that excess aldosteronism could play a clinically meaningful role in close to half of patients with hypertension, although Dr. Stowasser called this an “overestimate.” The new results also showed that “the single spot measurement of plasma aldosterone concentration, which clinicians have used for decades to screen for primary aldosteronism, is not merely useless but actually misleading. The authors cautioned readers about the uncertain representativeness of the study population to the U.S. population, but I believe that the findings are generalizable to the United States and elsewhere,” Dr. Funder wrote. “The central problem is that plasma aldosterone concentration is a very poor index of total daily aldosterone secretion. A single morning spot measurement of plasma aldosterone cannot take into account ultradian variation in aldosterone secretion.”
 

The importance of finding excess aldosterone

Identifying patients with hypertension and PA, as well as hypertensives with excess aldosterone production that may not meet the traditional definition of PA, is especially important because they are excellent candidates for two forms of targeted and very effective treatments that have a reliable and substantial impact on lowering blood pressure in these patients. One treatment is unilateral adrenal gland removal in patients who produce excess aldosterone because of benign adenomas in one adrenal gland, which accounts for “approximately 30%” of patients with PA. “Patients with suspected PA should have an opportunity to find out whether they have a unilateral variety and chance for surgical cure,” said Dr. Stowasser in an interview. “Patients with PA do far better in terms of blood pressure control, prevention of cardiovascular complications, and quality of life if they are treated specifically, either medically or particularly by surgery.”

The specific medical treatment he cited refers to one of the mineralocorticoid receptor antagonist (MRA) drugs, spironolactone and eplerenone (Inspra), because mineralocorticoid receptor blockade directly short-circuits the path by which aldosterone increases blood pressure. “We’re advocating earlier use of MRAs” for hypertensive patients identified with excess aldosterone production, said Dr. Carey. He noted that alternative, nonsteroidal MRAs, such as finerenone, have shown promise for efficacy levels similar to what spironolactone provides but without as many adverse effects because of greater receptor specificity. Finerenone and other nonsteroidal MRAs are all currently investigational. Spironolactone and eplerenone both cause hyperkalemia, although treatment with potassium binding agents can blunt the risk this poses. Spironolactone also causes bothersome adverse effects in men, including impotence and gynecomastia because of its action on androgen receptors, effects that diminished with eplerenone, but eplerenone is not as effective as spironolactone, Dr. Carey said.
 

Study details

The new study ran a post hoc analysis on data collected in five independent studies run at centers in four U.S. locations: Birmingham, Ala.; Boston; Charlottesville, Va.; and Salt Lake City. The studies included a total of 1,846 adults, mostly patients with hypertension of varying severity but also several hundred normotensive people. Data on 24-hour sodium excretion during an oral sodium suppression test were available for all participants, and the researchers excluded 831 people with an “inadequate” sodium balance of less than 190 mmol based on this metric, leaving a study population of 1,015. The researchers acknowledged the limitation that the study participants were not representative of the U.S. population.

The analysis included 289 normotensive people not on any blood pressure–lowering medications, and 239 fit the definition of having suppressed renin. The adjusted prevalence of aldosteronism at the level of at least 12 mcg excreted in a 24-hour urine specimen was 11% among all 289 normotensive subjects and 12% among the 239 with suppressed renin. When the definition of aldosteronism loosened to at least 10 mcg excreted during 24 hours the adjusted prevalence of excess aldosterone among normotensives increased to 19% among the entire group and 20% among those with suppressed renin. This finding may have identified a primordial phase of nascent hypertension that needs further study but may eventually provide a new scenario for intervention. “If a normotensive person has compliant arteries and healthy kidneys they can handle the excess salt and volume load of PA,” but when compensatory mechanisms start falling short through aging or other deteriorations, then blood pressure starts to rise, suggested Dr. Vaidya.
 

Whom to screen for aldosteronism and how

While several experts agreed these findings added to an existing and growing literature showing that PA is common and needs greater diagnostic attention, they differed on what this may mean for the specifics of screening and diagnosis, especially at the primary care level.

“Our results showed more explicitly that excess aldosterone exists on a broad severity spectrum and can’t be regarded as a categorical diagnosis that a patient either has or does not have. The hard part is figuring out where we should begin interventions,” said Dr. Vaidya.

In his editorial, Dr. Funder wrote that “much of the present guideline needs to be jettisoned, and radically reconstructed recommendations should be developed.”

One answer may be to apply a less stringent ARR threshold for further work-up. Dr. Stowasser’s program in Brisbane, as well as some other groups worldwide, use an ARR of at least 20 ng/dL as an indication of possible PA. “If you lower the cutoff to 20 [ng/dL], and ignore the plasma aldosterone level, then the ARR should pick up the great majority of patients with PA,” he said.

Another controversial aspect is whether aldosterone detection should be screened by 24-hour urine collection or by spot testing. In his editorial, Dr. Funder called spot testing “useless” and “misleading,” but Dr. Vaidya acknowledged that the 24-hour collection used in his current study is “not practical” for widespread use. Despite that, the Mayo Clinic in Rochester has focused on 24-hour urine collected “for more than 4 decades,” said Dr. Young, even though “a morning blood sample remains a simple screening test” that will catch “more than 95% of patients with PA” when combined with a plasma aldosterone threshold of 10 ng/dL. Dr. Stowasser noted that “patients don’t like” 24-hour collection, and not infrequently muck up collection” by forgetting to collect their entire 1-day output. Regardless of its shortcomings, 24-hour urine has the advantage of greater precision and accuracy than spot measurement, and using it on newly diagnosed hypertensive patients who also show renin suppression may be a viable approach, Dr. Carey suggested.

Regardless of exactly how guidelines for assessing aldosterone in hypertensive patients change, prospects seem ripe for some sort of revision and for greater participation and buy-in by primary care physicians than in the past. Dr. Carey, who also served as vice-chair of the American College of Cardiology and American Heart Association Task Force that wrote the most current U.S. guideline for managing hypertension, said it was too soon to revise that document, but the time had come to revise the Endocrine Society’s 2016 guideline for diagnosing and treating PA and to hash out the revision “in partnership” with one or more primary care societies. He also highlighted that publishing the current study in a high-profile primary care journal was an intentional effort to reach a large segment of the primary care community.

The new report “has the potential to change the current state of inertia” over wider PA diagnosis and targeted treatment “by being published in a widely read, major international journal,” commented Dr. Stowasser.

Dr. Vaidya has been a consultant to Catalys Pacific, Corcept Therapeutics, HRA Pharma, Orphagen, and Selenity Therapeutics. None of the other report coauthors had commercial disclosures, including Dr. Carey. Dr. Funder, Dr. Stowasser, and Dr. Young had no disclosures.

mzoler@mdedge.com

SOURCE: Brown JM et al. Ann Int Med. 2020 May 25. doi: 10.7326/M20-0065.
 

Aripiprazole lauroxil (AL) and paliperidone palmitate (PP) are effective and well tolerated for initiating treatment of schizophrenia in the hospital and for continuing outpatient treatment, results of a phase 3, double-blind trial show.

A total of 200 patients completed the study, 99 of whom received aripiprazole lauroxil (Aristada Initio) and 101 of whom received paliperidone palmitate (Invega Sustenna). The baseline Positive and Negative Syndrome scale (PANSS) total score for those who received aripiprazole lauroxil was 94.1 and 94.6 for those who received paliperidone palmitate, Peter J. Weiden, MD, of Alkermes, and his associates reported in the Journal of Clinical Psychiatry.

After 4 weeks of treatment, patients who received aripiprazole lauroxil saw a mean PANSS score reduction of 17.4 points; after 9 weeks the reduction was 19.8 points and was 23.3 points after 25 weeks. For patients who received paliperidone palmitate the reduction in PANSS score was 20.1 points at week 4, 22.5 points at week 9, and 21.7 points at week 25. The most common adverse events in both groups were injection-site pain (17.2% and 24.8%, respectively), increased weight (9.1% and 16.8%, respectively), and akathisia (9.1% and 10.9%, respectively).

“Acutely symptomatic patients with schizophrenia on a 2-month dose regimen of AL with the 1-day initiation regimen demonstrated safety and efficacy consistent with that seen in prior AL studies. ... The inclusion of PP provided an active control with known safety and efficacy that can also be rapidly initiated. Both regimens can be effectively used in patients with schizophrenia through the often challenging transition from acute hospitalization to outpatient continuation treatment, the investigators concluded.

The study was sponsored by Alkermes, manufacturer of Aristada Initio. Invega Sustenna is produced by Janssen Pharmaceuticals. The investigators reported being employed by, owning stock/options in, or receiving research support from Alkermes; two investigators reported receiving research support from numerous other companies.

lfranki@mdedge.com

SOURCE: Weiden PJ et al. J Clin Psychiatry. 2020 May 19. doi: 10.4088/JCP.19m13207.

Aripiprazole lauroxil (AL) and paliperidone palmitate (PP) are effective and well tolerated for initiating treatment of schizophrenia in the hospital and for continuing outpatient treatment, results of a phase 3, double-blind trial show.

A total of 200 patients completed the study, 99 of whom received aripiprazole lauroxil (Aristada Initio) and 101 of whom received paliperidone palmitate (Invega Sustenna). The baseline Positive and Negative Syndrome scale (PANSS) total score for those who received aripiprazole lauroxil was 94.1 and 94.6 for those who received paliperidone palmitate, Peter J. Weiden, MD, of Alkermes, and his associates reported in the Journal of Clinical Psychiatry.

After 4 weeks of treatment, patients who received aripiprazole lauroxil saw a mean PANSS score reduction of 17.4 points; after 9 weeks the reduction was 19.8 points and was 23.3 points after 25 weeks. For patients who received paliperidone palmitate the reduction in PANSS score was 20.1 points at week 4, 22.5 points at week 9, and 21.7 points at week 25. The most common adverse events in both groups were injection-site pain (17.2% and 24.8%, respectively), increased weight (9.1% and 16.8%, respectively), and akathisia (9.1% and 10.9%, respectively).

“Acutely symptomatic patients with schizophrenia on a 2-month dose regimen of AL with the 1-day initiation regimen demonstrated safety and efficacy consistent with that seen in prior AL studies. ... The inclusion of PP provided an active control with known safety and efficacy that can also be rapidly initiated. Both regimens can be effectively used in patients with schizophrenia through the often challenging transition from acute hospitalization to outpatient continuation treatment, the investigators concluded.

The study was sponsored by Alkermes, manufacturer of Aristada Initio. Invega Sustenna is produced by Janssen Pharmaceuticals. The investigators reported being employed by, owning stock/options in, or receiving research support from Alkermes; two investigators reported receiving research support from numerous other companies.

lfranki@mdedge.com

SOURCE: Weiden PJ et al. J Clin Psychiatry. 2020 May 19. doi: 10.4088/JCP.19m13207.

Aripiprazole lauroxil (AL) and paliperidone palmitate (PP) are effective and well tolerated for initiating treatment of schizophrenia in the hospital and for continuing outpatient treatment, results of a phase 3, double-blind trial show.

A total of 200 patients completed the study, 99 of whom received aripiprazole lauroxil (Aristada Initio) and 101 of whom received paliperidone palmitate (Invega Sustenna). The baseline Positive and Negative Syndrome scale (PANSS) total score for those who received aripiprazole lauroxil was 94.1 and 94.6 for those who received paliperidone palmitate, Peter J. Weiden, MD, of Alkermes, and his associates reported in the Journal of Clinical Psychiatry.

After 4 weeks of treatment, patients who received aripiprazole lauroxil saw a mean PANSS score reduction of 17.4 points; after 9 weeks the reduction was 19.8 points and was 23.3 points after 25 weeks. For patients who received paliperidone palmitate the reduction in PANSS score was 20.1 points at week 4, 22.5 points at week 9, and 21.7 points at week 25. The most common adverse events in both groups were injection-site pain (17.2% and 24.8%, respectively), increased weight (9.1% and 16.8%, respectively), and akathisia (9.1% and 10.9%, respectively).

“Acutely symptomatic patients with schizophrenia on a 2-month dose regimen of AL with the 1-day initiation regimen demonstrated safety and efficacy consistent with that seen in prior AL studies. ... The inclusion of PP provided an active control with known safety and efficacy that can also be rapidly initiated. Both regimens can be effectively used in patients with schizophrenia through the often challenging transition from acute hospitalization to outpatient continuation treatment, the investigators concluded.

The study was sponsored by Alkermes, manufacturer of Aristada Initio. Invega Sustenna is produced by Janssen Pharmaceuticals. The investigators reported being employed by, owning stock/options in, or receiving research support from Alkermes; two investigators reported receiving research support from numerous other companies.

lfranki@mdedge.com

SOURCE: Weiden PJ et al. J Clin Psychiatry. 2020 May 19. doi: 10.4088/JCP.19m13207.

Here are the stories our MDedge editors across specialties think you need to know about today:

Patients returning slowly to primary care

Patients are beginning to return for outpatient visits. These visits dropped 60% from prepandemic levels in early April, but have rebounded to about 30% less than baseline, on average, according to data from the Commonwealth Fund, Harvard University, and Phreesia. For primary care in particular, practices are seeing 25% fewer visits than they did in early March. But even with visits rebounding, primary care faces financial challenges. “Primary care practices are in dire straits, and their ability to treat patients is under threat,” said Melinda Abrams, MS, senior vice president of delivery system reform and international innovations for the Commonwealth Fund. “In the long term, an investment in primary care will ensure we have primary care, because we are concerned about its collapse.” READ MORE.
 

Are the eyes at risk from COVID-19?

Recently, Joseph Fair, PhD, an NBC News contributor, suggested that he may have become ill with COVID-19 because of a lack of eye protection on an airplane. From his hospital bed in New Orleans, he told the network that he had flown on a crowded plane where flight attendants weren’t wearing masks. He wore a mask and gloves, but no eye protection. “My best guess,” he told the interviewer, “was that it came through the eye route.” But experts still aren’t sure if infection through the eyes is possible. “I don’t think we can answer that question with 100% confidence at this time,” said H. Nida Sen, MD, director of the uveitis clinic at the National Eye Institute in Bethesda, Md., and a clinical investigator who is studying the effects of COVID-19 on the eye. But, she says, “I think it is biologically plausible.” READ MORE.

Social distancing shows harm in older adults

As physical distancing continues to be necessary to maintain the health of older adults during the COVID-19 pandemic, experts are raising the alarm about the harms of also being socially distant. Studies of previous quarantine periods as well as preliminary findings during the COVID-19 pandemic demonstrate an inverse relationship between social isolation measures and cognitive functioning in the elderly, according to Myrra Vernooij-Dassen, PhD, of Radboud University in Nigmegen, the Netherlands, and chair of INTERDEM, a pan-European network of dementia researchers. “A striking finding is that lack of social interaction is associated with incident dementia. Conversely, epidemiologic data indicate that a socially integrated lifestyle had a favorable influence on cognitive functioning and could even delay onset of dementia,” she said. READ MORE.

Americans are split on COVID-19 vaccination

As researchers race to produce a safe and effective vaccine against SARS-CoV-2, about half of Americans report they would get the vaccine if it were available. A recent poll, conducted by the AP-NORC Center for Public Affairs Research, found that 31% of respondents weren’t sure if they’d get a vaccine, and 20% said they’d refuse to get one. The poll was conducted May 14-18 and released May 27. Among respondents who said they don’t plan to get vaccinated, 70% said they’re concerned about side effects. Another 42% are worried about getting the coronavirus from the vaccine. READ MORE.

Biologic approved for atopic dermatitis

The Food and Drug Administration approved dupilumab for children aged 6-11 years with moderate to severe atopic dermatitis. This is the first biologic approved for atopic dermatitis in this age group. The new indication is for children whose disease is not adequately controlled with topical prescription therapies. READ MORE.

For more on COVID-19, visit our Resource Center. All of our latest news is available on MDedge.com.

Here are the stories our MDedge editors across specialties think you need to know about today:

Patients returning slowly to primary care

Patients are beginning to return for outpatient visits. These visits dropped 60% from prepandemic levels in early April, but have rebounded to about 30% less than baseline, on average, according to data from the Commonwealth Fund, Harvard University, and Phreesia. For primary care in particular, practices are seeing 25% fewer visits than they did in early March. But even with visits rebounding, primary care faces financial challenges. “Primary care practices are in dire straits, and their ability to treat patients is under threat,” said Melinda Abrams, MS, senior vice president of delivery system reform and international innovations for the Commonwealth Fund. “In the long term, an investment in primary care will ensure we have primary care, because we are concerned about its collapse.” READ MORE.
 

Are the eyes at risk from COVID-19?

Recently, Joseph Fair, PhD, an NBC News contributor, suggested that he may have become ill with COVID-19 because of a lack of eye protection on an airplane. From his hospital bed in New Orleans, he told the network that he had flown on a crowded plane where flight attendants weren’t wearing masks. He wore a mask and gloves, but no eye protection. “My best guess,” he told the interviewer, “was that it came through the eye route.” But experts still aren’t sure if infection through the eyes is possible. “I don’t think we can answer that question with 100% confidence at this time,” said H. Nida Sen, MD, director of the uveitis clinic at the National Eye Institute in Bethesda, Md., and a clinical investigator who is studying the effects of COVID-19 on the eye. But, she says, “I think it is biologically plausible.” READ MORE.

Social distancing shows harm in older adults

As physical distancing continues to be necessary to maintain the health of older adults during the COVID-19 pandemic, experts are raising the alarm about the harms of also being socially distant. Studies of previous quarantine periods as well as preliminary findings during the COVID-19 pandemic demonstrate an inverse relationship between social isolation measures and cognitive functioning in the elderly, according to Myrra Vernooij-Dassen, PhD, of Radboud University in Nigmegen, the Netherlands, and chair of INTERDEM, a pan-European network of dementia researchers. “A striking finding is that lack of social interaction is associated with incident dementia. Conversely, epidemiologic data indicate that a socially integrated lifestyle had a favorable influence on cognitive functioning and could even delay onset of dementia,” she said. READ MORE.

Americans are split on COVID-19 vaccination

As researchers race to produce a safe and effective vaccine against SARS-CoV-2, about half of Americans report they would get the vaccine if it were available. A recent poll, conducted by the AP-NORC Center for Public Affairs Research, found that 31% of respondents weren’t sure if they’d get a vaccine, and 20% said they’d refuse to get one. The poll was conducted May 14-18 and released May 27. Among respondents who said they don’t plan to get vaccinated, 70% said they’re concerned about side effects. Another 42% are worried about getting the coronavirus from the vaccine. READ MORE.

Biologic approved for atopic dermatitis

The Food and Drug Administration approved dupilumab for children aged 6-11 years with moderate to severe atopic dermatitis. This is the first biologic approved for atopic dermatitis in this age group. The new indication is for children whose disease is not adequately controlled with topical prescription therapies. READ MORE.

For more on COVID-19, visit our Resource Center. All of our latest news is available on MDedge.com.

Here are the stories our MDedge editors across specialties think you need to know about today:

Patients returning slowly to primary care

Patients are beginning to return for outpatient visits. These visits dropped 60% from prepandemic levels in early April, but have rebounded to about 30% less than baseline, on average, according to data from the Commonwealth Fund, Harvard University, and Phreesia. For primary care in particular, practices are seeing 25% fewer visits than they did in early March. But even with visits rebounding, primary care faces financial challenges. “Primary care practices are in dire straits, and their ability to treat patients is under threat,” said Melinda Abrams, MS, senior vice president of delivery system reform and international innovations for the Commonwealth Fund. “In the long term, an investment in primary care will ensure we have primary care, because we are concerned about its collapse.” READ MORE.
 

Are the eyes at risk from COVID-19?

Recently, Joseph Fair, PhD, an NBC News contributor, suggested that he may have become ill with COVID-19 because of a lack of eye protection on an airplane. From his hospital bed in New Orleans, he told the network that he had flown on a crowded plane where flight attendants weren’t wearing masks. He wore a mask and gloves, but no eye protection. “My best guess,” he told the interviewer, “was that it came through the eye route.” But experts still aren’t sure if infection through the eyes is possible. “I don’t think we can answer that question with 100% confidence at this time,” said H. Nida Sen, MD, director of the uveitis clinic at the National Eye Institute in Bethesda, Md., and a clinical investigator who is studying the effects of COVID-19 on the eye. But, she says, “I think it is biologically plausible.” READ MORE.

Social distancing shows harm in older adults

As physical distancing continues to be necessary to maintain the health of older adults during the COVID-19 pandemic, experts are raising the alarm about the harms of also being socially distant. Studies of previous quarantine periods as well as preliminary findings during the COVID-19 pandemic demonstrate an inverse relationship between social isolation measures and cognitive functioning in the elderly, according to Myrra Vernooij-Dassen, PhD, of Radboud University in Nigmegen, the Netherlands, and chair of INTERDEM, a pan-European network of dementia researchers. “A striking finding is that lack of social interaction is associated with incident dementia. Conversely, epidemiologic data indicate that a socially integrated lifestyle had a favorable influence on cognitive functioning and could even delay onset of dementia,” she said. READ MORE.

Americans are split on COVID-19 vaccination

As researchers race to produce a safe and effective vaccine against SARS-CoV-2, about half of Americans report they would get the vaccine if it were available. A recent poll, conducted by the AP-NORC Center for Public Affairs Research, found that 31% of respondents weren’t sure if they’d get a vaccine, and 20% said they’d refuse to get one. The poll was conducted May 14-18 and released May 27. Among respondents who said they don’t plan to get vaccinated, 70% said they’re concerned about side effects. Another 42% are worried about getting the coronavirus from the vaccine. READ MORE.

Biologic approved for atopic dermatitis

The Food and Drug Administration approved dupilumab for children aged 6-11 years with moderate to severe atopic dermatitis. This is the first biologic approved for atopic dermatitis in this age group. The new indication is for children whose disease is not adequately controlled with topical prescription therapies. READ MORE.

For more on COVID-19, visit our Resource Center. All of our latest news is available on MDedge.com.

The current standard frontline therapy for advanced epithelial ovarian, fallopian tube, and primary peritoneal cancer includes a combination of surgical cytoreduction and at least six cycles of platinum-based chemotherapy. While this achieves a complete clinical response (“remission”) in most, 85% of patients will recur and eventually succumb to the disease. This suggests that treatments are good at inducing remission, but poor at eradicating the disease altogether. This has motivated the consideration of maintenance therapy: extended treatment beyond completion of chemotherapy during the period of time when patients are clinically disease free.

Maintenance therapy is an appealing concept for clinicians who desperately want to “hold” their patients in a disease-free state for longer periods. It is also a profitable way to administer therapy as there is more compensation to the pharmaceutical industry from chronic, long-term drug administration rather than episodic treatment courses. However, the following question must be asked: Is this extended therapy worthwhile for all patients, and is it good value?

In the past 12 months, three major industry-sponsored clinical trials have been published (PRIMA, PAOLA-1, and VELIA)which suggest a benefit for all patients with advanced epithelial ovarian cancer in receiving prolonged poly (ADP-ribose) polymerase inhibitor (PARPi) therapy after primary chemotherapy.^1-3 This has resulted in Food and Drug Administration approval for some of these agents as maintenance therapy. Despite differences in the drugs tested and the timing of therapy, these studies observed that treatment of advanced ovarian cancer with the addition of a PARPi during and/or after carboplatin and paclitaxel chemotherapy for up to an additional 3 years resulted in a longer progression-free survival (PFS) of approximately 6 months. PFS is defined as the time to measurable recurrence or death. However, this positive effect was not equally distributed across the whole population; rather, it appeared to be created by a substantial response in a smaller subgroup.

PARP inhibitor therapies such as olaparib, niraparib, veliparib, and rucaparib target a family of enzymes that repair DNA and stabilize the human genome through the repair of single-stranded DNA breaks. Inhibiting these enzymes facilitates the accumulation of single-stranded breaks, allowing the development of double-strand breaks, which in turn cannot be repaired if the cell has deficient homologous recombination (HRD) such as through a germline or somatic BRCA mutation, or alternative relevant mutation that confers a similar effect. The opportunistic pairing of a drug interaction with a pathway specific to the cancer is an example of a targeted therapy.

In order to improve the value of cancer drug therapy, there has been emphasis by cooperative research groups, such as the Gynecologic Oncology Group, to study the efficacy of targeted therapies, such as PARPi, in patients identified by biomarkers such as tumors that possess germline or somatic HRD in whom they are most likely to work. This approach makes good common sense and promises to deliver a large magnitude of clinical benefit in a smaller focused population. Therefore, even if drug costs are high, the treatment may still have value. Consistent with that principle, the recently published VELIA, PRIMA, and PAOLA-1 trials all showed impressive benefit in PFS (on average 11-12 months) for the subgroup of patients with HRD. However, these studies were designed and funded by the pharmaceutical industry, and abandoned the principle of biomarker-driven targeted therapy. They did not limit their studies to the HRD-positive population most likely to benefit, but instead included and reported on the impact on all-comers (patients with both HRD and HR-proficient tumors). Subsequently their final conclusions could be extrapolated to the general population of ovarian cancer patients, and in doing so, a larger share of the marketplace.

Only 30% of the general population of ovarian, fallopian tube and primary peritoneal cancer patients carry a germline or somatic BRCA mutation and less than half carry this or alternative mutations which confer HRD. The remaining majority are HR-proficient tumors. However, the three study populations in the aforementioned trials were enriched for HRD tumors with 50%-60% subjects carrying germline or somatic HRD. Therefore, it is likely that the observed benefits in the “intent-to-treat” group were larger than what a clinician would observe in their patient population. Additionally, the large (11-12 month) gains in the HRD-positive group may have been so significant that they compensated for the subtle impact in the HR-proficient population (less than 3 months), resulting in an average total effect that, while being statistically significant for “all comers,” was actually only clinically significant for the HRD group. The positive impact for HRD tumors effectively boosted the results for the group as a whole.

The use of PFS as a primary endpoint raises another significant concern with the design of these PARPi maintenance trials. Much has been written about the importance of PFS as an endpoint for ovarian cancer because of confounding effects of subsequent therapy and to minimize the costs and duration of clinical trials.⁴ PFS is a quicker, less expensive endpoint to capture than overall survival. It usually correlates with overall survival, but typically only when there is a large magnitude of benefit in PFS. These arguments are fair when considering episodic drug therapies in the setting of measurable, active disease. However, maintenance therapy is given during a period of what patients think of as remission. Remission is valued by patients because it is a gateway to cure, and also because it is a time devoid of symptoms of disease, toxicity (therapeutic and financial), and the burden of frequent medical visits and interventions. While PFS is a measure of the length of remission, it is not a measure of cure. We should ask: What does it mean to a patient if she has a longer remission but needs to be on drug therapy (with its associated burdens and toxicities) in order to maintain that remission? We know that an increase in PFS with maintenance therapy does not always result in a commensurate increase in survival. One does not always precede the other. An example of this is the use of maintenance bevacizumab following upfront chemotherapy which improves PFS by 4 months, but is not associated with an increase in survival.⁵

When considering the value and ethics of maintenance therapy, it should be associated with a proven survival benefit or an improvement in quality of life. With respect to PARPi maintenance, we lack the data regarding the former, and have contrary evidence regarding the latter. In these three trials, PARPi maintenance was associated with significantly more toxicity than placebo including the commonly observed nausea and fatigue. Most of us would not like to be on a drug therapy for 3 years that made us feel nauseated or fatigued if it didn’t also increase our chance of cure or a longer life. While the significant PFS benefit of maintenance PARPi that is consistently observed in HRD-positive ovarian cancers suggests there will also likely be a clinically significant improvement in survival and cure in that specific subpopulation, this is less likely true for the majority of women with HR-proficient ovarian cancers. Time will tell this story, but as yet, we don’t know.

The use of maintenance PARPi therapy during and/or after primary cytotoxic chemotherapy for advanced epithelial ovarian, primary peritoneal, and fallopian tube cancer is associated with a substantial benefit in time to recurrence in a population with HRD tumors and a small benefit among the majority who don’t. However, it comes at the cost of toxicity at a time when patients would otherwise be free of disease and treatment. I propose that, until a survival benefit for all women has been observed, we should consider a targeted and biomarker-driven approach to maintenance PARPi prescription, favoring prescription for those with germline or somatic HRD mutations.

Dr. Rossi is assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She said she had no relevant financial disclosures. Email Dr. Rossi at obnews@mdedge.com.

References

1. González-Martín A et al. N Engl J Med. 2019 Dec 19;381(25):2391-402.

2. Ray-Coquard I et al. N Engl J Med. 2019 Dec 19;381(25):2416-28.

3. Coleman RL et al. N Engl J Med. 2019 Dec 19;381(25):2403-15.

4. Herzog TJ et al. Gynecol Oncol. 2014 Jan;132(1):8-17.

5. Tewari KS et al. J Clin Oncol. 2019 Sep 10;37(26):2317-28.

The current standard frontline therapy for advanced epithelial ovarian, fallopian tube, and primary peritoneal cancer includes a combination of surgical cytoreduction and at least six cycles of platinum-based chemotherapy. While this achieves a complete clinical response (“remission”) in most, 85% of patients will recur and eventually succumb to the disease. This suggests that treatments are good at inducing remission, but poor at eradicating the disease altogether. This has motivated the consideration of maintenance therapy: extended treatment beyond completion of chemotherapy during the period of time when patients are clinically disease free.

Maintenance therapy is an appealing concept for clinicians who desperately want to “hold” their patients in a disease-free state for longer periods. It is also a profitable way to administer therapy as there is more compensation to the pharmaceutical industry from chronic, long-term drug administration rather than episodic treatment courses. However, the following question must be asked: Is this extended therapy worthwhile for all patients, and is it good value?

In the past 12 months, three major industry-sponsored clinical trials have been published (PRIMA, PAOLA-1, and VELIA)which suggest a benefit for all patients with advanced epithelial ovarian cancer in receiving prolonged poly (ADP-ribose) polymerase inhibitor (PARPi) therapy after primary chemotherapy.^1-3 This has resulted in Food and Drug Administration approval for some of these agents as maintenance therapy. Despite differences in the drugs tested and the timing of therapy, these studies observed that treatment of advanced ovarian cancer with the addition of a PARPi during and/or after carboplatin and paclitaxel chemotherapy for up to an additional 3 years resulted in a longer progression-free survival (PFS) of approximately 6 months. PFS is defined as the time to measurable recurrence or death. However, this positive effect was not equally distributed across the whole population; rather, it appeared to be created by a substantial response in a smaller subgroup.

PARP inhibitor therapies such as olaparib, niraparib, veliparib, and rucaparib target a family of enzymes that repair DNA and stabilize the human genome through the repair of single-stranded DNA breaks. Inhibiting these enzymes facilitates the accumulation of single-stranded breaks, allowing the development of double-strand breaks, which in turn cannot be repaired if the cell has deficient homologous recombination (HRD) such as through a germline or somatic BRCA mutation, or alternative relevant mutation that confers a similar effect. The opportunistic pairing of a drug interaction with a pathway specific to the cancer is an example of a targeted therapy.

In order to improve the value of cancer drug therapy, there has been emphasis by cooperative research groups, such as the Gynecologic Oncology Group, to study the efficacy of targeted therapies, such as PARPi, in patients identified by biomarkers such as tumors that possess germline or somatic HRD in whom they are most likely to work. This approach makes good common sense and promises to deliver a large magnitude of clinical benefit in a smaller focused population. Therefore, even if drug costs are high, the treatment may still have value. Consistent with that principle, the recently published VELIA, PRIMA, and PAOLA-1 trials all showed impressive benefit in PFS (on average 11-12 months) for the subgroup of patients with HRD. However, these studies were designed and funded by the pharmaceutical industry, and abandoned the principle of biomarker-driven targeted therapy. They did not limit their studies to the HRD-positive population most likely to benefit, but instead included and reported on the impact on all-comers (patients with both HRD and HR-proficient tumors). Subsequently their final conclusions could be extrapolated to the general population of ovarian cancer patients, and in doing so, a larger share of the marketplace.

Only 30% of the general population of ovarian, fallopian tube and primary peritoneal cancer patients carry a germline or somatic BRCA mutation and less than half carry this or alternative mutations which confer HRD. The remaining majority are HR-proficient tumors. However, the three study populations in the aforementioned trials were enriched for HRD tumors with 50%-60% subjects carrying germline or somatic HRD. Therefore, it is likely that the observed benefits in the “intent-to-treat” group were larger than what a clinician would observe in their patient population. Additionally, the large (11-12 month) gains in the HRD-positive group may have been so significant that they compensated for the subtle impact in the HR-proficient population (less than 3 months), resulting in an average total effect that, while being statistically significant for “all comers,” was actually only clinically significant for the HRD group. The positive impact for HRD tumors effectively boosted the results for the group as a whole.

The use of PFS as a primary endpoint raises another significant concern with the design of these PARPi maintenance trials. Much has been written about the importance of PFS as an endpoint for ovarian cancer because of confounding effects of subsequent therapy and to minimize the costs and duration of clinical trials.⁴ PFS is a quicker, less expensive endpoint to capture than overall survival. It usually correlates with overall survival, but typically only when there is a large magnitude of benefit in PFS. These arguments are fair when considering episodic drug therapies in the setting of measurable, active disease. However, maintenance therapy is given during a period of what patients think of as remission. Remission is valued by patients because it is a gateway to cure, and also because it is a time devoid of symptoms of disease, toxicity (therapeutic and financial), and the burden of frequent medical visits and interventions. While PFS is a measure of the length of remission, it is not a measure of cure. We should ask: What does it mean to a patient if she has a longer remission but needs to be on drug therapy (with its associated burdens and toxicities) in order to maintain that remission? We know that an increase in PFS with maintenance therapy does not always result in a commensurate increase in survival. One does not always precede the other. An example of this is the use of maintenance bevacizumab following upfront chemotherapy which improves PFS by 4 months, but is not associated with an increase in survival.⁵

When considering the value and ethics of maintenance therapy, it should be associated with a proven survival benefit or an improvement in quality of life. With respect to PARPi maintenance, we lack the data regarding the former, and have contrary evidence regarding the latter. In these three trials, PARPi maintenance was associated with significantly more toxicity than placebo including the commonly observed nausea and fatigue. Most of us would not like to be on a drug therapy for 3 years that made us feel nauseated or fatigued if it didn’t also increase our chance of cure or a longer life. While the significant PFS benefit of maintenance PARPi that is consistently observed in HRD-positive ovarian cancers suggests there will also likely be a clinically significant improvement in survival and cure in that specific subpopulation, this is less likely true for the majority of women with HR-proficient ovarian cancers. Time will tell this story, but as yet, we don’t know.

The use of maintenance PARPi therapy during and/or after primary cytotoxic chemotherapy for advanced epithelial ovarian, primary peritoneal, and fallopian tube cancer is associated with a substantial benefit in time to recurrence in a population with HRD tumors and a small benefit among the majority who don’t. However, it comes at the cost of toxicity at a time when patients would otherwise be free of disease and treatment. I propose that, until a survival benefit for all women has been observed, we should consider a targeted and biomarker-driven approach to maintenance PARPi prescription, favoring prescription for those with germline or somatic HRD mutations.

Dr. Rossi is assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She said she had no relevant financial disclosures. Email Dr. Rossi at obnews@mdedge.com.

References

1. González-Martín A et al. N Engl J Med. 2019 Dec 19;381(25):2391-402.

2. Ray-Coquard I et al. N Engl J Med. 2019 Dec 19;381(25):2416-28.

3. Coleman RL et al. N Engl J Med. 2019 Dec 19;381(25):2403-15.

4. Herzog TJ et al. Gynecol Oncol. 2014 Jan;132(1):8-17.

5. Tewari KS et al. J Clin Oncol. 2019 Sep 10;37(26):2317-28.

The current standard frontline therapy for advanced epithelial ovarian, fallopian tube, and primary peritoneal cancer includes a combination of surgical cytoreduction and at least six cycles of platinum-based chemotherapy. While this achieves a complete clinical response (“remission”) in most, 85% of patients will recur and eventually succumb to the disease. This suggests that treatments are good at inducing remission, but poor at eradicating the disease altogether. This has motivated the consideration of maintenance therapy: extended treatment beyond completion of chemotherapy during the period of time when patients are clinically disease free.

Maintenance therapy is an appealing concept for clinicians who desperately want to “hold” their patients in a disease-free state for longer periods. It is also a profitable way to administer therapy as there is more compensation to the pharmaceutical industry from chronic, long-term drug administration rather than episodic treatment courses. However, the following question must be asked: Is this extended therapy worthwhile for all patients, and is it good value?

In the past 12 months, three major industry-sponsored clinical trials have been published (PRIMA, PAOLA-1, and VELIA)which suggest a benefit for all patients with advanced epithelial ovarian cancer in receiving prolonged poly (ADP-ribose) polymerase inhibitor (PARPi) therapy after primary chemotherapy.^1-3 This has resulted in Food and Drug Administration approval for some of these agents as maintenance therapy. Despite differences in the drugs tested and the timing of therapy, these studies observed that treatment of advanced ovarian cancer with the addition of a PARPi during and/or after carboplatin and paclitaxel chemotherapy for up to an additional 3 years resulted in a longer progression-free survival (PFS) of approximately 6 months. PFS is defined as the time to measurable recurrence or death. However, this positive effect was not equally distributed across the whole population; rather, it appeared to be created by a substantial response in a smaller subgroup.

PARP inhibitor therapies such as olaparib, niraparib, veliparib, and rucaparib target a family of enzymes that repair DNA and stabilize the human genome through the repair of single-stranded DNA breaks. Inhibiting these enzymes facilitates the accumulation of single-stranded breaks, allowing the development of double-strand breaks, which in turn cannot be repaired if the cell has deficient homologous recombination (HRD) such as through a germline or somatic BRCA mutation, or alternative relevant mutation that confers a similar effect. The opportunistic pairing of a drug interaction with a pathway specific to the cancer is an example of a targeted therapy.

In order to improve the value of cancer drug therapy, there has been emphasis by cooperative research groups, such as the Gynecologic Oncology Group, to study the efficacy of targeted therapies, such as PARPi, in patients identified by biomarkers such as tumors that possess germline or somatic HRD in whom they are most likely to work. This approach makes good common sense and promises to deliver a large magnitude of clinical benefit in a smaller focused population. Therefore, even if drug costs are high, the treatment may still have value. Consistent with that principle, the recently published VELIA, PRIMA, and PAOLA-1 trials all showed impressive benefit in PFS (on average 11-12 months) for the subgroup of patients with HRD. However, these studies were designed and funded by the pharmaceutical industry, and abandoned the principle of biomarker-driven targeted therapy. They did not limit their studies to the HRD-positive population most likely to benefit, but instead included and reported on the impact on all-comers (patients with both HRD and HR-proficient tumors). Subsequently their final conclusions could be extrapolated to the general population of ovarian cancer patients, and in doing so, a larger share of the marketplace.

Only 30% of the general population of ovarian, fallopian tube and primary peritoneal cancer patients carry a germline or somatic BRCA mutation and less than half carry this or alternative mutations which confer HRD. The remaining majority are HR-proficient tumors. However, the three study populations in the aforementioned trials were enriched for HRD tumors with 50%-60% subjects carrying germline or somatic HRD. Therefore, it is likely that the observed benefits in the “intent-to-treat” group were larger than what a clinician would observe in their patient population. Additionally, the large (11-12 month) gains in the HRD-positive group may have been so significant that they compensated for the subtle impact in the HR-proficient population (less than 3 months), resulting in an average total effect that, while being statistically significant for “all comers,” was actually only clinically significant for the HRD group. The positive impact for HRD tumors effectively boosted the results for the group as a whole.

The use of PFS as a primary endpoint raises another significant concern with the design of these PARPi maintenance trials. Much has been written about the importance of PFS as an endpoint for ovarian cancer because of confounding effects of subsequent therapy and to minimize the costs and duration of clinical trials.⁴ PFS is a quicker, less expensive endpoint to capture than overall survival. It usually correlates with overall survival, but typically only when there is a large magnitude of benefit in PFS. These arguments are fair when considering episodic drug therapies in the setting of measurable, active disease. However, maintenance therapy is given during a period of what patients think of as remission. Remission is valued by patients because it is a gateway to cure, and also because it is a time devoid of symptoms of disease, toxicity (therapeutic and financial), and the burden of frequent medical visits and interventions. While PFS is a measure of the length of remission, it is not a measure of cure. We should ask: What does it mean to a patient if she has a longer remission but needs to be on drug therapy (with its associated burdens and toxicities) in order to maintain that remission? We know that an increase in PFS with maintenance therapy does not always result in a commensurate increase in survival. One does not always precede the other. An example of this is the use of maintenance bevacizumab following upfront chemotherapy which improves PFS by 4 months, but is not associated with an increase in survival.⁵

When considering the value and ethics of maintenance therapy, it should be associated with a proven survival benefit or an improvement in quality of life. With respect to PARPi maintenance, we lack the data regarding the former, and have contrary evidence regarding the latter. In these three trials, PARPi maintenance was associated with significantly more toxicity than placebo including the commonly observed nausea and fatigue. Most of us would not like to be on a drug therapy for 3 years that made us feel nauseated or fatigued if it didn’t also increase our chance of cure or a longer life. While the significant PFS benefit of maintenance PARPi that is consistently observed in HRD-positive ovarian cancers suggests there will also likely be a clinically significant improvement in survival and cure in that specific subpopulation, this is less likely true for the majority of women with HR-proficient ovarian cancers. Time will tell this story, but as yet, we don’t know.

The use of maintenance PARPi therapy during and/or after primary cytotoxic chemotherapy for advanced epithelial ovarian, primary peritoneal, and fallopian tube cancer is associated with a substantial benefit in time to recurrence in a population with HRD tumors and a small benefit among the majority who don’t. However, it comes at the cost of toxicity at a time when patients would otherwise be free of disease and treatment. I propose that, until a survival benefit for all women has been observed, we should consider a targeted and biomarker-driven approach to maintenance PARPi prescription, favoring prescription for those with germline or somatic HRD mutations.

Dr. Rossi is assistant professor in the division of gynecologic oncology at the University of North Carolina at Chapel Hill. She said she had no relevant financial disclosures. Email Dr. Rossi at obnews@mdedge.com.

References

1. González-Martín A et al. N Engl J Med. 2019 Dec 19;381(25):2391-402.

2. Ray-Coquard I et al. N Engl J Med. 2019 Dec 19;381(25):2416-28.

3. Coleman RL et al. N Engl J Med. 2019 Dec 19;381(25):2403-15.

4. Herzog TJ et al. Gynecol Oncol. 2014 Jan;132(1):8-17.

5. Tewari KS et al. J Clin Oncol. 2019 Sep 10;37(26):2317-28.

The Food and Drug Administration has approved brigatinib (Alunbrig) to treat adults with ALK-positive metastatic non–small cell lung cancer (NSCLC) as detected by an FDA-approved test.

The FDA also approved the Vysis ALK Break Apart FISH Probe Kit as a companion diagnostic for brigatinib.

Brigatinib and the companion diagnostic were both evaluated in the ALTA 1L trial (NCT02737501). The trial enrolled adults with advanced ALK-positive NSCLC who had not previously received an ALK-targeted therapy. Patients had to have an ALK rearrangement based on a local standard of care test.

Clinical samples from trial participants were retrospectively tested with the Vysis ALK Break Apart FISH Probe Kit. Of the 275 patients enrolled in the trial, 239 were ALK positive according to the test. Results were negative for 20 patients and unavailable for 16 patients.

Patients were randomized to receive brigatinib at 180 mg once daily with a 7-day lead-in at 90 mg once daily (n = 137) or crizotinib at 250 mg twice daily (n = 138).

The estimated median progression-free survival was 24 months in the brigatinib arm and 11 months in the crizotinib arm (hazard ratio, 0.49; P < .0001). The overall response rate was 74% in the brigatinib arm and 62% in the crizotinib arm.

The most common adverse events in the brigatinib arm, occurring in at least 20% of patients, were diarrhea, fatigue, nausea, rash, cough, myalgia, headache, hypertension, vomiting, abdominal pain, pruritus, back pain, and dyspnea.

Serious adverse events occurred in 33% of patients in the brigatinib arm, and fatal adverse events included in 2.9%. The fatal events were pneumonia (1.5%), cerebrovascular accident (0.7%), and multiple organ dysfunction syndrome (0.7%).

For more details on the ALTA 1L trial, see the full prescribing information for brigatinib.

The approval of brigatinib was granted to ARIAD Pharmaceuticals. The approval of the Vysis ALK Break Apart FISH Probe Kit was granted to Abbott Molecular.

The Food and Drug Administration has approved brigatinib (Alunbrig) to treat adults with ALK-positive metastatic non–small cell lung cancer (NSCLC) as detected by an FDA-approved test.

The FDA also approved the Vysis ALK Break Apart FISH Probe Kit as a companion diagnostic for brigatinib.

Brigatinib and the companion diagnostic were both evaluated in the ALTA 1L trial (NCT02737501). The trial enrolled adults with advanced ALK-positive NSCLC who had not previously received an ALK-targeted therapy. Patients had to have an ALK rearrangement based on a local standard of care test.

Clinical samples from trial participants were retrospectively tested with the Vysis ALK Break Apart FISH Probe Kit. Of the 275 patients enrolled in the trial, 239 were ALK positive according to the test. Results were negative for 20 patients and unavailable for 16 patients.

Patients were randomized to receive brigatinib at 180 mg once daily with a 7-day lead-in at 90 mg once daily (n = 137) or crizotinib at 250 mg twice daily (n = 138).

The estimated median progression-free survival was 24 months in the brigatinib arm and 11 months in the crizotinib arm (hazard ratio, 0.49; P < .0001). The overall response rate was 74% in the brigatinib arm and 62% in the crizotinib arm.

The most common adverse events in the brigatinib arm, occurring in at least 20% of patients, were diarrhea, fatigue, nausea, rash, cough, myalgia, headache, hypertension, vomiting, abdominal pain, pruritus, back pain, and dyspnea.

Serious adverse events occurred in 33% of patients in the brigatinib arm, and fatal adverse events included in 2.9%. The fatal events were pneumonia (1.5%), cerebrovascular accident (0.7%), and multiple organ dysfunction syndrome (0.7%).

For more details on the ALTA 1L trial, see the full prescribing information for brigatinib.

The approval of brigatinib was granted to ARIAD Pharmaceuticals. The approval of the Vysis ALK Break Apart FISH Probe Kit was granted to Abbott Molecular.

The Food and Drug Administration has approved brigatinib (Alunbrig) to treat adults with ALK-positive metastatic non–small cell lung cancer (NSCLC) as detected by an FDA-approved test.

The FDA also approved the Vysis ALK Break Apart FISH Probe Kit as a companion diagnostic for brigatinib.

Brigatinib and the companion diagnostic were both evaluated in the ALTA 1L trial (NCT02737501). The trial enrolled adults with advanced ALK-positive NSCLC who had not previously received an ALK-targeted therapy. Patients had to have an ALK rearrangement based on a local standard of care test.

Clinical samples from trial participants were retrospectively tested with the Vysis ALK Break Apart FISH Probe Kit. Of the 275 patients enrolled in the trial, 239 were ALK positive according to the test. Results were negative for 20 patients and unavailable for 16 patients.

Patients were randomized to receive brigatinib at 180 mg once daily with a 7-day lead-in at 90 mg once daily (n = 137) or crizotinib at 250 mg twice daily (n = 138).

The estimated median progression-free survival was 24 months in the brigatinib arm and 11 months in the crizotinib arm (hazard ratio, 0.49; P < .0001). The overall response rate was 74% in the brigatinib arm and 62% in the crizotinib arm.

The most common adverse events in the brigatinib arm, occurring in at least 20% of patients, were diarrhea, fatigue, nausea, rash, cough, myalgia, headache, hypertension, vomiting, abdominal pain, pruritus, back pain, and dyspnea.

Serious adverse events occurred in 33% of patients in the brigatinib arm, and fatal adverse events included in 2.9%. The fatal events were pneumonia (1.5%), cerebrovascular accident (0.7%), and multiple organ dysfunction syndrome (0.7%).

For more details on the ALTA 1L trial, see the full prescribing information for brigatinib.

The approval of brigatinib was granted to ARIAD Pharmaceuticals. The approval of the Vysis ALK Break Apart FISH Probe Kit was granted to Abbott Molecular.

The calcitonin gene-related peptide monoclonal antibody galcanezumab (Emgality, Lilly) compared favorably to placebo for reducing the number of average monthly migraine days in a new study of people with treatment-resistant migraine headaches. “The patients included in our study had previously tried multiple migraine preventive treatments that didn’t work for them. These patients are left with limited treatment options to help with the debilitating pain of migraine,” said lead author Holland C. Detke, PhD, senior clinical research advisor at Eli Lilly and Company Biomedicines.

Participants who took the drug experienced “a rapid reduction in migraine days starting as early as month 1, and continuing through the 6 months of the study,” Dr. Detke said.

The treatment group reported an average 4.0 fewer monthly migraine days at 3 months, for example, compared with a baseline of 13.4 days, whereas the placebo group decreased an average 1.29 days from a similar baseline of 13.0 migraine days.

Dr. Detke presented these and other results of the open-label phase of the CONQUER phase 3 trial online as part of the 2020 American Academy of Neurology Science Highlights.

The investigators enrolled 462 adults with episodic or chronic migraine. All participants previously failed two to four migraine treatments because of insufficient efficacy or issues around tolerability or safety. At month 0, 232 people were randomly assigned to galcanezumab and another 230 to placebo injections. At 3 months, 449 participants received a galcanezumab injection as part of the open-label treatment phase.

Participants were an average 48 years old, approximately 86% were women, and 82% were white. At baseline, mean Migraine Specific Quality of Life Role Function Restrictive (MSQ RFR) domain score was 45, “indicating significant impairment in functioning,” Dr. Detke said. At the same time, mean Migraine Disability Assessment Test (MIDAS) total score was 51, “indicating quite severe disability.”
 

Significant outcomes

The decrease in migraine days at 3 months – 4.0 days with treatment versus 1.29 with placebo – was statistically significant (P < .0001). During the open-label phase, participants who switched from placebo “essentially catch up to where the previously treated people were,” Dr. Detke said. At 6 months, the decrease in average monthly headache days was 5.60 in the initial galcanezumab group versus 5.24 in the initial placebo group.

Significant differences at 3 months versus baseline were observed in participants who received galcanezumab when investigators assessed reduction in 50% or more, 75% or more, or 100% of mean monthly migraine days. No such significant decreases were seen in the placebo group.

Treatment-emergent adverse events reported in the open-label phase included nasopharyngitis in 4.2%, injection site pain in 3.8%, and injection site erythema in 2.7%. Five participants discontinued during the open-label phase because of adverse events.

The results of the study suggest galcanezumab “should be considered as a treatment option for patients who have not had success with previous treatments,” Dr. Detke said.
 

Multiple strengths of study

“It is encouraging that galcanezumab works in patients who have failed prior reduction strategies,” A. Laine Green, MD, a neurologist at Dartmouth-Hitchcock Medical Center in Lebanon, N.H., said when asked to comment.

This study did not look at patients who have failed more than four previous reduction strategies, he added. “Clinically we see many of these patients. To be fair, no one has studied this group using the monoclonal antibodies.”

Dr. Green noted several strengths of the study. The groups were similar, there were few dropouts during the open-label extension, and there were no unexpected side effects or adverse events. “Those who got placebo caught up to those who received active treatment in the double-blind phase,” he said. “It is also nice to see patient reported outcomes improved as headaches improve. This adds consistency to the results.”

One caveat, Dr. Green noted, is “with open-label extensions, there is always the potential for bias because patients know what treatment they are receiving.”

Overall [the study] gives hope that patients who have failed previous reduction strategies may respond to the newer monoclonal antibodies.”
 

Aligns with previous findings

The results are “the same as any other long-term extension study of a drug for migraine,” Stephen Silberstein, MD, said when asked to comment. “The longer one takes it, the better you get.”

The research also confirms that if you switch patients taking placebo to an active treatment, they get better, added Dr. Silberstein, director of the Headache Center at Jefferson Health in Philadelphia.

Because they are injections, agents such as galcanezumab, other monoclonal antibodies, and botulinum toxin offer better compliance for headache compared with small molecule medications that require daily oral dosing, he added.

Eli Lilly and Company funded the study. Dr. Holland Detke is a Lilly employee. Dr. Green collaborated with Lilly on a poster for the AHS scientific meeting on a similar topic but did not receive compensation. Up until August 2019, he served as a consultant for Lilly, Novartis, Teva and Allergan. Dr. Green is also a member of the Medscape and American Headache Society Migraine Steering Committee. Dr. Silberstein is a member of the advisory board and consultant for Lilly.

Source: Detke HC et al. AAN 2020. Abstract 43625.

The calcitonin gene-related peptide monoclonal antibody galcanezumab (Emgality, Lilly) compared favorably to placebo for reducing the number of average monthly migraine days in a new study of people with treatment-resistant migraine headaches. “The patients included in our study had previously tried multiple migraine preventive treatments that didn’t work for them. These patients are left with limited treatment options to help with the debilitating pain of migraine,” said lead author Holland C. Detke, PhD, senior clinical research advisor at Eli Lilly and Company Biomedicines.

Participants who took the drug experienced “a rapid reduction in migraine days starting as early as month 1, and continuing through the 6 months of the study,” Dr. Detke said.

The treatment group reported an average 4.0 fewer monthly migraine days at 3 months, for example, compared with a baseline of 13.4 days, whereas the placebo group decreased an average 1.29 days from a similar baseline of 13.0 migraine days.

Dr. Detke presented these and other results of the open-label phase of the CONQUER phase 3 trial online as part of the 2020 American Academy of Neurology Science Highlights.

The investigators enrolled 462 adults with episodic or chronic migraine. All participants previously failed two to four migraine treatments because of insufficient efficacy or issues around tolerability or safety. At month 0, 232 people were randomly assigned to galcanezumab and another 230 to placebo injections. At 3 months, 449 participants received a galcanezumab injection as part of the open-label treatment phase.

Participants were an average 48 years old, approximately 86% were women, and 82% were white. At baseline, mean Migraine Specific Quality of Life Role Function Restrictive (MSQ RFR) domain score was 45, “indicating significant impairment in functioning,” Dr. Detke said. At the same time, mean Migraine Disability Assessment Test (MIDAS) total score was 51, “indicating quite severe disability.”
 

Significant outcomes

The decrease in migraine days at 3 months – 4.0 days with treatment versus 1.29 with placebo – was statistically significant (P < .0001). During the open-label phase, participants who switched from placebo “essentially catch up to where the previously treated people were,” Dr. Detke said. At 6 months, the decrease in average monthly headache days was 5.60 in the initial galcanezumab group versus 5.24 in the initial placebo group.

Significant differences at 3 months versus baseline were observed in participants who received galcanezumab when investigators assessed reduction in 50% or more, 75% or more, or 100% of mean monthly migraine days. No such significant decreases were seen in the placebo group.

Treatment-emergent adverse events reported in the open-label phase included nasopharyngitis in 4.2%, injection site pain in 3.8%, and injection site erythema in 2.7%. Five participants discontinued during the open-label phase because of adverse events.

The results of the study suggest galcanezumab “should be considered as a treatment option for patients who have not had success with previous treatments,” Dr. Detke said.
 

Multiple strengths of study

“It is encouraging that galcanezumab works in patients who have failed prior reduction strategies,” A. Laine Green, MD, a neurologist at Dartmouth-Hitchcock Medical Center in Lebanon, N.H., said when asked to comment.

This study did not look at patients who have failed more than four previous reduction strategies, he added. “Clinically we see many of these patients. To be fair, no one has studied this group using the monoclonal antibodies.”

Dr. Green noted several strengths of the study. The groups were similar, there were few dropouts during the open-label extension, and there were no unexpected side effects or adverse events. “Those who got placebo caught up to those who received active treatment in the double-blind phase,” he said. “It is also nice to see patient reported outcomes improved as headaches improve. This adds consistency to the results.”

One caveat, Dr. Green noted, is “with open-label extensions, there is always the potential for bias because patients know what treatment they are receiving.”

Overall [the study] gives hope that patients who have failed previous reduction strategies may respond to the newer monoclonal antibodies.”
 

Aligns with previous findings

The results are “the same as any other long-term extension study of a drug for migraine,” Stephen Silberstein, MD, said when asked to comment. “The longer one takes it, the better you get.”

The research also confirms that if you switch patients taking placebo to an active treatment, they get better, added Dr. Silberstein, director of the Headache Center at Jefferson Health in Philadelphia.

Because they are injections, agents such as galcanezumab, other monoclonal antibodies, and botulinum toxin offer better compliance for headache compared with small molecule medications that require daily oral dosing, he added.

Eli Lilly and Company funded the study. Dr. Holland Detke is a Lilly employee. Dr. Green collaborated with Lilly on a poster for the AHS scientific meeting on a similar topic but did not receive compensation. Up until August 2019, he served as a consultant for Lilly, Novartis, Teva and Allergan. Dr. Green is also a member of the Medscape and American Headache Society Migraine Steering Committee. Dr. Silberstein is a member of the advisory board and consultant for Lilly.

Source: Detke HC et al. AAN 2020. Abstract 43625.

The calcitonin gene-related peptide monoclonal antibody galcanezumab (Emgality, Lilly) compared favorably to placebo for reducing the number of average monthly migraine days in a new study of people with treatment-resistant migraine headaches. “The patients included in our study had previously tried multiple migraine preventive treatments that didn’t work for them. These patients are left with limited treatment options to help with the debilitating pain of migraine,” said lead author Holland C. Detke, PhD, senior clinical research advisor at Eli Lilly and Company Biomedicines.

Participants who took the drug experienced “a rapid reduction in migraine days starting as early as month 1, and continuing through the 6 months of the study,” Dr. Detke said.

The treatment group reported an average 4.0 fewer monthly migraine days at 3 months, for example, compared with a baseline of 13.4 days, whereas the placebo group decreased an average 1.29 days from a similar baseline of 13.0 migraine days.

Dr. Detke presented these and other results of the open-label phase of the CONQUER phase 3 trial online as part of the 2020 American Academy of Neurology Science Highlights.

The investigators enrolled 462 adults with episodic or chronic migraine. All participants previously failed two to four migraine treatments because of insufficient efficacy or issues around tolerability or safety. At month 0, 232 people were randomly assigned to galcanezumab and another 230 to placebo injections. At 3 months, 449 participants received a galcanezumab injection as part of the open-label treatment phase.

Participants were an average 48 years old, approximately 86% were women, and 82% were white. At baseline, mean Migraine Specific Quality of Life Role Function Restrictive (MSQ RFR) domain score was 45, “indicating significant impairment in functioning,” Dr. Detke said. At the same time, mean Migraine Disability Assessment Test (MIDAS) total score was 51, “indicating quite severe disability.”
 

Significant outcomes

The decrease in migraine days at 3 months – 4.0 days with treatment versus 1.29 with placebo – was statistically significant (P < .0001). During the open-label phase, participants who switched from placebo “essentially catch up to where the previously treated people were,” Dr. Detke said. At 6 months, the decrease in average monthly headache days was 5.60 in the initial galcanezumab group versus 5.24 in the initial placebo group.

Significant differences at 3 months versus baseline were observed in participants who received galcanezumab when investigators assessed reduction in 50% or more, 75% or more, or 100% of mean monthly migraine days. No such significant decreases were seen in the placebo group.

Treatment-emergent adverse events reported in the open-label phase included nasopharyngitis in 4.2%, injection site pain in 3.8%, and injection site erythema in 2.7%. Five participants discontinued during the open-label phase because of adverse events.

The results of the study suggest galcanezumab “should be considered as a treatment option for patients who have not had success with previous treatments,” Dr. Detke said.
 

Multiple strengths of study

“It is encouraging that galcanezumab works in patients who have failed prior reduction strategies,” A. Laine Green, MD, a neurologist at Dartmouth-Hitchcock Medical Center in Lebanon, N.H., said when asked to comment.

This study did not look at patients who have failed more than four previous reduction strategies, he added. “Clinically we see many of these patients. To be fair, no one has studied this group using the monoclonal antibodies.”

Dr. Green noted several strengths of the study. The groups were similar, there were few dropouts during the open-label extension, and there were no unexpected side effects or adverse events. “Those who got placebo caught up to those who received active treatment in the double-blind phase,” he said. “It is also nice to see patient reported outcomes improved as headaches improve. This adds consistency to the results.”

One caveat, Dr. Green noted, is “with open-label extensions, there is always the potential for bias because patients know what treatment they are receiving.”

Overall [the study] gives hope that patients who have failed previous reduction strategies may respond to the newer monoclonal antibodies.”
 

Aligns with previous findings

The results are “the same as any other long-term extension study of a drug for migraine,” Stephen Silberstein, MD, said when asked to comment. “The longer one takes it, the better you get.”

The research also confirms that if you switch patients taking placebo to an active treatment, they get better, added Dr. Silberstein, director of the Headache Center at Jefferson Health in Philadelphia.

Because they are injections, agents such as galcanezumab, other monoclonal antibodies, and botulinum toxin offer better compliance for headache compared with small molecule medications that require daily oral dosing, he added.

Eli Lilly and Company funded the study. Dr. Holland Detke is a Lilly employee. Dr. Green collaborated with Lilly on a poster for the AHS scientific meeting on a similar topic but did not receive compensation. Up until August 2019, he served as a consultant for Lilly, Novartis, Teva and Allergan. Dr. Green is also a member of the Medscape and American Headache Society Migraine Steering Committee. Dr. Silberstein is a member of the advisory board and consultant for Lilly.

Source: Detke HC et al. AAN 2020. Abstract 43625.

Pediatric dermatologists overwhelmingly say that the COVID-19 pandemic has affected how they prescribe and monitor immunosuppressive medications for inflammatory skin diseases, according to a task force survey designed to offer guidance to specialists and nonspecialists faced with tough choices about risks.

Some 87% reported that they were reducing the frequency of lab monitoring for some medications, while more than half said they had reached out to patients and their families to discuss the implications of continuing or stopping a drug.

Virtually all – 97% – said that the COVID-19 crisis had affected their decision to initiate immunosuppressive medications, with 84% saying the decision depended on a patient’s risk factors for contracting COVID-19 infection, and also the potential consequences of infection while treated, compared with the risks of not optimally treating the skin condition.

To develop a consensus-based guidance for clinicians, published online April 22 in Pediatric Dermatology, Kelly Cordoro, MD, professor of dermatology at the University of California, San Francisco, assembled a task force of pediatric dermatologists at academic institutions (the Pediatric Dermatology COVID-19 Response Task Force). Together with Sean Reynolds, MD, a pediatric dermatology fellow at UCSF and colleagues, they issued a survey to the 37 members of the task force with questions on how the pandemic has affected their prescribing decisions and certain therapies specifically. All the recipients responded.

The dermatologists were asked about conventional systemic and biologic medications. Most felt confident in continuing biologics, with 78% saying they would keep patients with no signs of COVID-19 exposure or infection on tumor necrosis factor (TNF) inhibitors. More than 90% of respondents said they would continue patients on dupilumab, as well as anti–interleukin (IL)–17, anti–IL-12/23, and anti–IL-23 therapies.

Responses varied more on approaches to the nonbiologic treatments. Fewer than half (46%) said they would continue patients without apparent COVID-19 exposure on systemic steroids, with another 46% saying it depended on the clinical context.

For other systemic therapies, respondents were more likely to want to continue their patients with no signs or symptoms of COVID-19 on methotrexate and apremilast (78% and 83%, respectively) than others (mycophenolate mofetil, azathioprine, cyclosporine, and JAK inhibitors), which saw between 50% and 60% support in the survey.

Patients on any immunosuppressive medications with likely exposure to COVID-19 or who test positive for the virus should be temporarily taken off their medications, the majority concurred. Exceptions were for systemic steroids, which must be tapered. And a significant minority of the dermatologists said that they would continue apremilast or dupilumab (24% and 16%, respectively) in the event of a confirmed COVID-19 infection.

In an interview, Dr. Cordoro commented that, even in normal times, most systemic or biological immunosuppressive treatments are used off-label by pediatric dermatologists. “There’s no way this could have been an evidence-based document, as we didn’t have the data to drive this. Many of the medications have been tested in children but not necessarily for dermatologic indications; some are chemotherapy agents or drugs used in rheumatologic diseases.”

The COVID-19 pandemic complicated an already difficult decision-making process, she said.

The researchers cautioned against attempting to make decisions about medications based on data on other infections from clinical trials. “Infection data from standard infections that were identified and watched for in clinical trials really still has no bearing on COVID-19 because it’s such a different virus,” Dr. Cordoro said.

And while some immunosuppressive medications could potentially attenuate a SARS-CoV-2–induced cytokine storm, “we certainly don’t assume this is necessarily going to help.”

The authors advised that physicians anxious about initiating an immunosuppressive treatment should take into consideration whether early intervention could “prevent permanent physical impairment or disfigurement” in diseases such as erythrodermic pustular psoriasis or rapidly progressive linear morphea.

Other diseases, such as atopic dermatitis, “may be acceptably, though not optimally, managed with topical and other home-based therapeutic options” during the pandemic, they wrote.

Dr. Cordoro commented that, given how fast new findings are emerging from the pandemic, the guidance on medications could change. “We will know so much more 3 months from now,” she said. And while there are no formal plans to reissue the survey, “we’re maintaining communication and will have some kind of follow up” with the academic dermatologists.

“If we recognize any signals that are counter to what we say in this work we will immediately let people know,” she said.

The researchers received no outside funding for their study. Of the study’s 24 coauthors, nine disclosed financial relationships with industry.

SOURCE: Add the first auSOURCE: Reynolds et al. Pediatr Dermatol. 2020. doi: 10.1111/pde.14202.

Pediatric dermatologists overwhelmingly say that the COVID-19 pandemic has affected how they prescribe and monitor immunosuppressive medications for inflammatory skin diseases, according to a task force survey designed to offer guidance to specialists and nonspecialists faced with tough choices about risks.

Some 87% reported that they were reducing the frequency of lab monitoring for some medications, while more than half said they had reached out to patients and their families to discuss the implications of continuing or stopping a drug.

Virtually all – 97% – said that the COVID-19 crisis had affected their decision to initiate immunosuppressive medications, with 84% saying the decision depended on a patient’s risk factors for contracting COVID-19 infection, and also the potential consequences of infection while treated, compared with the risks of not optimally treating the skin condition.

To develop a consensus-based guidance for clinicians, published online April 22 in Pediatric Dermatology, Kelly Cordoro, MD, professor of dermatology at the University of California, San Francisco, assembled a task force of pediatric dermatologists at academic institutions (the Pediatric Dermatology COVID-19 Response Task Force). Together with Sean Reynolds, MD, a pediatric dermatology fellow at UCSF and colleagues, they issued a survey to the 37 members of the task force with questions on how the pandemic has affected their prescribing decisions and certain therapies specifically. All the recipients responded.

The dermatologists were asked about conventional systemic and biologic medications. Most felt confident in continuing biologics, with 78% saying they would keep patients with no signs of COVID-19 exposure or infection on tumor necrosis factor (TNF) inhibitors. More than 90% of respondents said they would continue patients on dupilumab, as well as anti–interleukin (IL)–17, anti–IL-12/23, and anti–IL-23 therapies.

Responses varied more on approaches to the nonbiologic treatments. Fewer than half (46%) said they would continue patients without apparent COVID-19 exposure on systemic steroids, with another 46% saying it depended on the clinical context.

For other systemic therapies, respondents were more likely to want to continue their patients with no signs or symptoms of COVID-19 on methotrexate and apremilast (78% and 83%, respectively) than others (mycophenolate mofetil, azathioprine, cyclosporine, and JAK inhibitors), which saw between 50% and 60% support in the survey.

Patients on any immunosuppressive medications with likely exposure to COVID-19 or who test positive for the virus should be temporarily taken off their medications, the majority concurred. Exceptions were for systemic steroids, which must be tapered. And a significant minority of the dermatologists said that they would continue apremilast or dupilumab (24% and 16%, respectively) in the event of a confirmed COVID-19 infection.

In an interview, Dr. Cordoro commented that, even in normal times, most systemic or biological immunosuppressive treatments are used off-label by pediatric dermatologists. “There’s no way this could have been an evidence-based document, as we didn’t have the data to drive this. Many of the medications have been tested in children but not necessarily for dermatologic indications; some are chemotherapy agents or drugs used in rheumatologic diseases.”

The COVID-19 pandemic complicated an already difficult decision-making process, she said.

The researchers cautioned against attempting to make decisions about medications based on data on other infections from clinical trials. “Infection data from standard infections that were identified and watched for in clinical trials really still has no bearing on COVID-19 because it’s such a different virus,” Dr. Cordoro said.

And while some immunosuppressive medications could potentially attenuate a SARS-CoV-2–induced cytokine storm, “we certainly don’t assume this is necessarily going to help.”

The authors advised that physicians anxious about initiating an immunosuppressive treatment should take into consideration whether early intervention could “prevent permanent physical impairment or disfigurement” in diseases such as erythrodermic pustular psoriasis or rapidly progressive linear morphea.

Other diseases, such as atopic dermatitis, “may be acceptably, though not optimally, managed with topical and other home-based therapeutic options” during the pandemic, they wrote.

Dr. Cordoro commented that, given how fast new findings are emerging from the pandemic, the guidance on medications could change. “We will know so much more 3 months from now,” she said. And while there are no formal plans to reissue the survey, “we’re maintaining communication and will have some kind of follow up” with the academic dermatologists.

“If we recognize any signals that are counter to what we say in this work we will immediately let people know,” she said.

The researchers received no outside funding for their study. Of the study’s 24 coauthors, nine disclosed financial relationships with industry.

SOURCE: Add the first auSOURCE: Reynolds et al. Pediatr Dermatol. 2020. doi: 10.1111/pde.14202.

Pediatric dermatologists overwhelmingly say that the COVID-19 pandemic has affected how they prescribe and monitor immunosuppressive medications for inflammatory skin diseases, according to a task force survey designed to offer guidance to specialists and nonspecialists faced with tough choices about risks.

Some 87% reported that they were reducing the frequency of lab monitoring for some medications, while more than half said they had reached out to patients and their families to discuss the implications of continuing or stopping a drug.

Virtually all – 97% – said that the COVID-19 crisis had affected their decision to initiate immunosuppressive medications, with 84% saying the decision depended on a patient’s risk factors for contracting COVID-19 infection, and also the potential consequences of infection while treated, compared with the risks of not optimally treating the skin condition.

To develop a consensus-based guidance for clinicians, published online April 22 in Pediatric Dermatology, Kelly Cordoro, MD, professor of dermatology at the University of California, San Francisco, assembled a task force of pediatric dermatologists at academic institutions (the Pediatric Dermatology COVID-19 Response Task Force). Together with Sean Reynolds, MD, a pediatric dermatology fellow at UCSF and colleagues, they issued a survey to the 37 members of the task force with questions on how the pandemic has affected their prescribing decisions and certain therapies specifically. All the recipients responded.

The dermatologists were asked about conventional systemic and biologic medications. Most felt confident in continuing biologics, with 78% saying they would keep patients with no signs of COVID-19 exposure or infection on tumor necrosis factor (TNF) inhibitors. More than 90% of respondents said they would continue patients on dupilumab, as well as anti–interleukin (IL)–17, anti–IL-12/23, and anti–IL-23 therapies.

Responses varied more on approaches to the nonbiologic treatments. Fewer than half (46%) said they would continue patients without apparent COVID-19 exposure on systemic steroids, with another 46% saying it depended on the clinical context.

For other systemic therapies, respondents were more likely to want to continue their patients with no signs or symptoms of COVID-19 on methotrexate and apremilast (78% and 83%, respectively) than others (mycophenolate mofetil, azathioprine, cyclosporine, and JAK inhibitors), which saw between 50% and 60% support in the survey.

Patients on any immunosuppressive medications with likely exposure to COVID-19 or who test positive for the virus should be temporarily taken off their medications, the majority concurred. Exceptions were for systemic steroids, which must be tapered. And a significant minority of the dermatologists said that they would continue apremilast or dupilumab (24% and 16%, respectively) in the event of a confirmed COVID-19 infection.

In an interview, Dr. Cordoro commented that, even in normal times, most systemic or biological immunosuppressive treatments are used off-label by pediatric dermatologists. “There’s no way this could have been an evidence-based document, as we didn’t have the data to drive this. Many of the medications have been tested in children but not necessarily for dermatologic indications; some are chemotherapy agents or drugs used in rheumatologic diseases.”

The COVID-19 pandemic complicated an already difficult decision-making process, she said.

The researchers cautioned against attempting to make decisions about medications based on data on other infections from clinical trials. “Infection data from standard infections that were identified and watched for in clinical trials really still has no bearing on COVID-19 because it’s such a different virus,” Dr. Cordoro said.

And while some immunosuppressive medications could potentially attenuate a SARS-CoV-2–induced cytokine storm, “we certainly don’t assume this is necessarily going to help.”

The authors advised that physicians anxious about initiating an immunosuppressive treatment should take into consideration whether early intervention could “prevent permanent physical impairment or disfigurement” in diseases such as erythrodermic pustular psoriasis or rapidly progressive linear morphea.

Other diseases, such as atopic dermatitis, “may be acceptably, though not optimally, managed with topical and other home-based therapeutic options” during the pandemic, they wrote.

Dr. Cordoro commented that, given how fast new findings are emerging from the pandemic, the guidance on medications could change. “We will know so much more 3 months from now,” she said. And while there are no formal plans to reissue the survey, “we’re maintaining communication and will have some kind of follow up” with the academic dermatologists.

“If we recognize any signals that are counter to what we say in this work we will immediately let people know,” she said.

The researchers received no outside funding for their study. Of the study’s 24 coauthors, nine disclosed financial relationships with industry.

SOURCE: Add the first auSOURCE: Reynolds et al. Pediatr Dermatol. 2020. doi: 10.1111/pde.14202.

Hyperkalemia is the most common adverse event associated with spironolactone use in women, but is uncommon in women aged 45 years or younger, according to new research.

Spironolactone, which is approved to treat heart failure, hypertension, edema, and primary hyperaldosteronism, has antagonistic effects on progesterone and androgen receptors and has been used as an off-label treatment for acne in women. “Numerous guidelines have recommended its off-label use for acne therapy to avoid antibiotic resistance and potential side effects,” wrote Yu Wang of Stony Brook (N.Y.) University and Shari R. Lipner MD, PhD, of Weill Cornell Medicine, New York. Their report is in the International Journal of Women’s Dermatology.

In a retrospective study, the investigators analyzed 7,920 adverse events with spironolactone reported by women of all ages between Jan. 1, 1969, and Dec. 30, 2018, to the Food and Drug Administration’s Adverse Event Reporting System database, for all indications. The most common adverse event was hyperkalemia, reported in 16.1%, followed by kidney injury (15.2%) and drug interactions (9%). Of the 1,272 cases of hyperkalemia reported, 25 occurred in women aged 45 years or younger; 59.3% occurred in women aged 65-85 years.

While spironolactone prescribing information was not available, the investigators compared yearly reports of adverse events with annual public interest in spironolactone using the Google Trends search term spironolactone and annual scholarly mentions of spironolactone in the Altmetric database. There was a strong correlation between the number of cases reported to the FDA and the Google Trends search (Spearman coefficient, 0.94; P less than .001) and to the Altmetric database (Spearman coefficient, 0.64; P less than .01).

Noting that hyperkalemia is “exceptionally uncommon” in women aged 45 years and younger, the investigators concluded that “in the absence of risk factors for hyperkalemia or reduced renal function, potassium laboratory monitoring is unnecessary in younger females taking spironolactone.” Because the incidence increases with age, “interval laboratory monitoring is recommended for females older than 45 years old,” they noted.

Limitations of the study, they noted, include the retrospective design and no available data before 1969. “In addition, since the [FDA Adverse Event Reporting System] data does not differentiate whether spironolactone was prescribed for heart failure, hypertension, edema, primary hyperaldosteronism, or for acne,” the study could not control for these or other confounding comorbidities or associated therapies.

“For future studies, it is important to analyze drug interactions more carefully to determine which other medications may potentiate the risk for hyperkalemia in patients taking spironolactone. It is also important to quantitate overall U.S. prescription data to better understand the relative frequency of these adverse effects reported to the FDA,” they wrote.

The investigators reported that they had no conflicts of interest; the study had no funding.

lfranki@mdedge.com

SOURCE: Wang Y, Lipner SR. Int J Womens Dermatol. 2020 May 18. doi: 10.1016/j.ijwd.2020.05.002.

Hyperkalemia is the most common adverse event associated with spironolactone use in women, but is uncommon in women aged 45 years or younger, according to new research.

Spironolactone, which is approved to treat heart failure, hypertension, edema, and primary hyperaldosteronism, has antagonistic effects on progesterone and androgen receptors and has been used as an off-label treatment for acne in women. “Numerous guidelines have recommended its off-label use for acne therapy to avoid antibiotic resistance and potential side effects,” wrote Yu Wang of Stony Brook (N.Y.) University and Shari R. Lipner MD, PhD, of Weill Cornell Medicine, New York. Their report is in the International Journal of Women’s Dermatology.

In a retrospective study, the investigators analyzed 7,920 adverse events with spironolactone reported by women of all ages between Jan. 1, 1969, and Dec. 30, 2018, to the Food and Drug Administration’s Adverse Event Reporting System database, for all indications. The most common adverse event was hyperkalemia, reported in 16.1%, followed by kidney injury (15.2%) and drug interactions (9%). Of the 1,272 cases of hyperkalemia reported, 25 occurred in women aged 45 years or younger; 59.3% occurred in women aged 65-85 years.

While spironolactone prescribing information was not available, the investigators compared yearly reports of adverse events with annual public interest in spironolactone using the Google Trends search term spironolactone and annual scholarly mentions of spironolactone in the Altmetric database. There was a strong correlation between the number of cases reported to the FDA and the Google Trends search (Spearman coefficient, 0.94; P less than .001) and to the Altmetric database (Spearman coefficient, 0.64; P less than .01).

Noting that hyperkalemia is “exceptionally uncommon” in women aged 45 years and younger, the investigators concluded that “in the absence of risk factors for hyperkalemia or reduced renal function, potassium laboratory monitoring is unnecessary in younger females taking spironolactone.” Because the incidence increases with age, “interval laboratory monitoring is recommended for females older than 45 years old,” they noted.

Limitations of the study, they noted, include the retrospective design and no available data before 1969. “In addition, since the [FDA Adverse Event Reporting System] data does not differentiate whether spironolactone was prescribed for heart failure, hypertension, edema, primary hyperaldosteronism, or for acne,” the study could not control for these or other confounding comorbidities or associated therapies.

“For future studies, it is important to analyze drug interactions more carefully to determine which other medications may potentiate the risk for hyperkalemia in patients taking spironolactone. It is also important to quantitate overall U.S. prescription data to better understand the relative frequency of these adverse effects reported to the FDA,” they wrote.

The investigators reported that they had no conflicts of interest; the study had no funding.

lfranki@mdedge.com

SOURCE: Wang Y, Lipner SR. Int J Womens Dermatol. 2020 May 18. doi: 10.1016/j.ijwd.2020.05.002.

Hyperkalemia is the most common adverse event associated with spironolactone use in women, but is uncommon in women aged 45 years or younger, according to new research.

Spironolactone, which is approved to treat heart failure, hypertension, edema, and primary hyperaldosteronism, has antagonistic effects on progesterone and androgen receptors and has been used as an off-label treatment for acne in women. “Numerous guidelines have recommended its off-label use for acne therapy to avoid antibiotic resistance and potential side effects,” wrote Yu Wang of Stony Brook (N.Y.) University and Shari R. Lipner MD, PhD, of Weill Cornell Medicine, New York. Their report is in the International Journal of Women’s Dermatology.

In a retrospective study, the investigators analyzed 7,920 adverse events with spironolactone reported by women of all ages between Jan. 1, 1969, and Dec. 30, 2018, to the Food and Drug Administration’s Adverse Event Reporting System database, for all indications. The most common adverse event was hyperkalemia, reported in 16.1%, followed by kidney injury (15.2%) and drug interactions (9%). Of the 1,272 cases of hyperkalemia reported, 25 occurred in women aged 45 years or younger; 59.3% occurred in women aged 65-85 years.

While spironolactone prescribing information was not available, the investigators compared yearly reports of adverse events with annual public interest in spironolactone using the Google Trends search term spironolactone and annual scholarly mentions of spironolactone in the Altmetric database. There was a strong correlation between the number of cases reported to the FDA and the Google Trends search (Spearman coefficient, 0.94; P less than .001) and to the Altmetric database (Spearman coefficient, 0.64; P less than .01).

Noting that hyperkalemia is “exceptionally uncommon” in women aged 45 years and younger, the investigators concluded that “in the absence of risk factors for hyperkalemia or reduced renal function, potassium laboratory monitoring is unnecessary in younger females taking spironolactone.” Because the incidence increases with age, “interval laboratory monitoring is recommended for females older than 45 years old,” they noted.

Limitations of the study, they noted, include the retrospective design and no available data before 1969. “In addition, since the [FDA Adverse Event Reporting System] data does not differentiate whether spironolactone was prescribed for heart failure, hypertension, edema, primary hyperaldosteronism, or for acne,” the study could not control for these or other confounding comorbidities or associated therapies.

“For future studies, it is important to analyze drug interactions more carefully to determine which other medications may potentiate the risk for hyperkalemia in patients taking spironolactone. It is also important to quantitate overall U.S. prescription data to better understand the relative frequency of these adverse effects reported to the FDA,” they wrote.

The investigators reported that they had no conflicts of interest; the study had no funding.

lfranki@mdedge.com

SOURCE: Wang Y, Lipner SR. Int J Womens Dermatol. 2020 May 18. doi: 10.1016/j.ijwd.2020.05.002.

After more than 8 months of development, Crayola is ready to release a set of specially formulated crayons that are “designed to mirror and represent over 40 global skin tones across the world.”

Crayola

“With the world growing more diverse than ever before, Crayola hopes our new Colors of the World crayons will increase representation and foster a greater sense of belonging and acceptance,” CEO Rich Wuerthele said in a written statement.

Crayola

The company partnered with a cosmetic industry foundation-color expert to create “colors that step down from light to deep shades across rose, almond, and golden undertones, resulting in a 24 global shade palette that authentically reflects the full spectrum of human complexions,” according to Crayola’s statement. The 24- and 32-count Colors of the World packs will start reaching stores in July. The pack of 32 crayons includes the 24 skin colors along with 4 hair and 4 eye colors.

rfranki@mdedge.com

After more than 8 months of development, Crayola is ready to release a set of specially formulated crayons that are “designed to mirror and represent over 40 global skin tones across the world.”

Crayola

“With the world growing more diverse than ever before, Crayola hopes our new Colors of the World crayons will increase representation and foster a greater sense of belonging and acceptance,” CEO Rich Wuerthele said in a written statement.

Crayola

The company partnered with a cosmetic industry foundation-color expert to create “colors that step down from light to deep shades across rose, almond, and golden undertones, resulting in a 24 global shade palette that authentically reflects the full spectrum of human complexions,” according to Crayola’s statement. The 24- and 32-count Colors of the World packs will start reaching stores in July. The pack of 32 crayons includes the 24 skin colors along with 4 hair and 4 eye colors.

rfranki@mdedge.com

After more than 8 months of development, Crayola is ready to release a set of specially formulated crayons that are “designed to mirror and represent over 40 global skin tones across the world.”

Crayola

“With the world growing more diverse than ever before, Crayola hopes our new Colors of the World crayons will increase representation and foster a greater sense of belonging and acceptance,” CEO Rich Wuerthele said in a written statement.

Crayola

The company partnered with a cosmetic industry foundation-color expert to create “colors that step down from light to deep shades across rose, almond, and golden undertones, resulting in a 24 global shade palette that authentically reflects the full spectrum of human complexions,” according to Crayola’s statement. The 24- and 32-count Colors of the World packs will start reaching stores in July. The pack of 32 crayons includes the 24 skin colors along with 4 hair and 4 eye colors.

rfranki@mdedge.com